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Chauhan R, Mohan M, Mannan A, Devi S, Singh TG. Unravelling the role of Interleukin-12 in Neuroinflammatory mechanisms: Pathogenic pathways linking Neuroinflammation to neuropsychiatric disorders. Int Immunopharmacol 2025; 156:114654. [PMID: 40294470 DOI: 10.1016/j.intimp.2025.114654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Neuropsychiatric disorders are clinically characterized conditions involving both neurology and psychiatry, arising from dysfunctioning of cerebral function, or indirect effects of extra cerebral disease. Neuropsychiatric disorders tend to influence emotions, mood, and brain functioning. Growing evidence indicates that the etiology of these disorders is not confined to neuronal abnormalities but extends to include inflammation. While the underlying mechanism of these disorders is still in its infancy, recent data highlights the significant role of neuroinflammation in their pathophysiology. Neuroinflammation concerns the inflammation within the neural tissue characterized by alteration in astrocytes, cytokines, microglia, and chemokines within the central nervous system. The cytokines include IFN-γ, IL-1β, IL-2, IL4, IL-6, IL-8, IL-10, and IL-12. This review focuses on interleukin-12 (IL-12), a key mediator of neuroinflammation, and its potential involvement in neuropsychiatric disorders. IL-12 promotes neuroinflammation and influences neurotransmitter systems. Additionally, it also affects the HPA axis, impairs neuroplasticity, and activates microglia by interacting with TLR, JAK-STAT, PI3K/Akt, GSK-3, NMDA, MAPK, PKC, VEGFR, ROCK, and Wnt signaling pathways and elicit its role in ND. In this review, we dwell on the current evidence supporting IL-12's pathogenic role and explore the possible mechanisms by which it contributes to the development and progression of these conditions. This review aims to provide insights that may aid in future therapeutic strategies by illuminating the interplay between neuroinflammation and neuropsychiatric disorders.
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Affiliation(s)
- Rupali Chauhan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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2
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Ayyadevara VSSA, Wertheim G, Gaur S, Chukinas JA, Loftus JP, Lee SJ, Kumar A, Swaminathan S, Bhansali RS, Childers W, Geng H, Milne TA, Hua X, Bernt KM, Besson T, Shi J, Crispino JD, Carroll M, Tasian SK, Hurtz C. DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition. Leukemia 2025; 39:1078-1089. [PMID: 40148558 PMCID: PMC12055583 DOI: 10.1038/s41375-025-02575-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/18/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.
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Affiliation(s)
- V S S Abhinav Ayyadevara
- Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Gerald Wertheim
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Shikha Gaur
- Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - John A Chukinas
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Joseph P Loftus
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Sung June Lee
- Department of Systems Biology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Anil Kumar
- Department of Systems Biology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Srividya Swaminathan
- Department of Systems Biology, City of Hope Beckman Research Institute, Duarte, CA, USA
- Department of Pediatrics, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Rahul S Bhansali
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Wayne Childers
- Moulder Center for Drug Discovery, Temple University School of Pharmacy, Philadelphia, PA, USA
| | - Huimin Geng
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Thomas A Milne
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Xianxin Hua
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kathrin M Bernt
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics and Abramson Cancer Center at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Thierry Besson
- Univ Rouen Normandie, INSA Rouen Normandie, CNRS, Institut CARMeN UMR 6064, Rouen, France
| | - Junwei Shi
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - John D Crispino
- Division of Experimental Hematology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Martin Carroll
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Sarah K Tasian
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Pediatrics and Abramson Cancer Center at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
| | - Christian Hurtz
- Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
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Pizzi M, Lorenzi L, Scarmozzino F, Albertini E, Balzarini P, Sbaraglia M, Santoro L, Chiudinelli M, Mussolin L, Carraro E, Cutrone C, Casola S, Pellegrini V, Nalio S, Bonaldi L, Pillon M, Dei Tos AP. Reactive Bcl2-positive germinal centres in paediatric tonsils: expanding the spectrum of lymphoma mimickers in children and adolescents. Histopathology 2025. [PMID: 40289261 DOI: 10.1111/his.15460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/27/2025] [Accepted: 04/06/2025] [Indexed: 04/30/2025]
Abstract
AIMS Bcl2-positive germinal centres (GCs) have never been documented in reactive lymphoid hyperplasia (RLH). Here we describe such phenomenon in paediatric chronic tonsillitis (PCT), addressing the differential diagnosis with paediatric lymphomas. METHODS AND RESULTS Six PCT cases with Bcl2-positive GCs were retrieved from a retrospective series of 166 tonsillectomies from children and adolescents. Clinical-pathological data were collected, also considering the status of IG rearrangements and BCL2 translocations. PCT with Bcl2-positive GCs mostly occurred in males (5/6 cases; median age: 5 years). Histologically, tonsil architecture was preserved and Bcl2 positivity was documented in a minority of GCs. Bcl2-positive GCs expressed CD10 and Bcl6 and had a high proliferation index. All cases had polyclonal IG rearrangements without evidence of monotypic kappa and lambda chains by RNAscope. BCL2 translocations were lacking in all the cases. CONCLUSION Bcl2-positive GCs in PCT are a rare and benign phenomenon, expanding the spectrum of lymphoma-mimicking paediatric RLH.
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Affiliation(s)
- Marco Pizzi
- Pathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Luisa Lorenzi
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Federico Scarmozzino
- Pathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Emma Albertini
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Piera Balzarini
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Marta Sbaraglia
- Pathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Luisa Santoro
- Pathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | | | - Lara Mussolin
- Oncohematology Unit, Department of Woman and Child Health, University of Padua School of Medicine, Padua, Italy
| | - Elisa Carraro
- Oncohematology Unit, Department of Woman and Child Health, University of Padua School of Medicine, Padua, Italy
| | - Cesare Cutrone
- Otolaryngology Unit, Department of Neurosciences, University of Padua School of Medicine, Padua, Italy
| | - Stefano Casola
- Genetics of B cells and Lymphoma unit, IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Vilma Pellegrini
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Silvia Nalio
- Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Laura Bonaldi
- Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Marta Pillon
- Oncohematology Unit, Department of Woman and Child Health, University of Padua School of Medicine, Padua, Italy
| | - Angelo Paolo Dei Tos
- Pathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
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Nix MN, Gourisankar S, Sarott RC, Dwyer BG, Nettles SA, Martinez MM, Abuzaid H, Yang H, Wang Y, Simanauskaite JM, Romero BA, Jones HM, Krokhotin A, Lowensohn TN, Chen L, Low C, Davis MM, Fernandez D, Zhang T, Green MR, Hinshaw SM, Gray NS, Crabtree GR. A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.14.643404. [PMID: 40166243 PMCID: PMC11956963 DOI: 10.1101/2025.03.14.643404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.
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Affiliation(s)
- Meredith N. Nix
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
- Department of Chemistry, Stanford University, Stanford, CA, USA
| | - Sai Gourisankar
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Roman C. Sarott
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Brendan G. Dwyer
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | | | - Michael M. Martinez
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Hind Abuzaid
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Haopeng Yang
- Department of Lymphoma- & Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yanlan Wang
- Department of Pathology, Stanford University, Stanford, CA, USA
| | | | - Bryan A. Romero
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Hannah M. Jones
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | | | | | - Lei Chen
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Cara Low
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Mark M. Davis
- Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Daniel Fernandez
- Macromolecular Structure, Nucleus at Sarafan ChEM-H, Stanford University, Stanford, CA, USA
| | - Tinghu Zhang
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Michael R. Green
- Department of Lymphoma- & Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stephen M. Hinshaw
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Nathanael S. Gray
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Gerald R. Crabtree
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Developmental Biology, Stanford University, Stanford, CA, USA
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Sodsook W, Kobayashi Y, Kamimoto H, Niki Y, Yokoo K, Chantarawaratit PO, Moriyama K. Roles of B-cell lymphoma 6 in orthodontic tooth movement of rat molars. Eur J Orthod 2025; 47:cjaf006. [PMID: 39917993 DOI: 10.1093/ejo/cjaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
INTRODUCTION B-cell lymphoma 6 (Bcl6) inhibits osteoclast differentiation in vitro; however, its role in orthodontic tooth movement (OTM) remains unclear. This study aimed to investigate the role of Bcl6 in OTM of rat molars. MATERIALS AND METHODS OTM was performed on the maxillary first molars of male rats using nickel-titanium coil springs (25 gf) for 14 days with or without local injection of FX1 (50 mg/kg), a Bcl6 inhibitor (n = 10 per group). Micro-computed tomography (CT) images were used to analyse OTM distance and bone morphometric parameters. Immunohistochemistry (IHC) determined Bcl6 expression and tartrate-resistant acid phosphatase staining (TRAP) staining assessed osteoclast differentiation. TRAP staining, and reverse transcription-quantitative polymerase chain reaction determined the effect of FX1 (1 μM) on in vitro rat osteoclast differentiation. The effect of FX1 on cell proliferation and Smad4 expression in periodontal ligament (PDL) cells was determined. RESULTS Administration of FX1 significantly increased OTM distance and decreased the bone/tissue volume compared with vehicle treatment. IHC staining showed that the vehicle-OTM group had higher expression of Bcl6 than the FX1-OTM group. The number of osteoclasts on the compression side was significantly higher in the FX1-OTM group than that in the vehicle-OTM group. FX1 enhanced osteoclast differentiation and expression of Nfatc1, Dc-stamp, and Ctsk mRNA in osteoclasts in vitro. FX1 significantly promotes PDL cell proliferation in vivo and in vitro. LIMITATIONS We evaluated only 14 days of OTM. CONCLUSIONS Bcl6 may play an important role in OTM via modulation of osteoclast differentiation and PDL cell proliferation.
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Affiliation(s)
- Wasupol Sodsook
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
- Department of Orthodontics, Faculty of Dentistry, Chulalongkorn University, 34 Henri Dunant Road, Pathum Wan, Bangkok, Thailand
- Institute of Science Tokyo and Chulalongkorn University International Joint Degree Doctor of Philosophy Program in Orthodontics
| | - Yukiho Kobayashi
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Hiroyuki Kamimoto
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Yuki Niki
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Koji Yokoo
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
| | - Pintu-On Chantarawaratit
- Department of Orthodontics, Faculty of Dentistry, Chulalongkorn University, 34 Henri Dunant Road, Pathum Wan, Bangkok, Thailand
| | - Keiji Moriyama
- Department of Maxillofacial Orthognathics, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan
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Liu PC, Huang SY, Lin KI, Hsieh SL, Leu CM. Suppression of NF-κB and downstream XBP1 by DcR3 contributes to a decrease in antibody secretion. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:72-84. [PMID: 40073262 DOI: 10.1093/jimmun/vkae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/24/2024] [Indexed: 03/14/2025]
Abstract
Decoy receptor 3 (DcR3), a soluble receptor in the tumor necrosis factor receptor superfamily, regulates the functions of monocytes, macrophages, dendritic cells, and T cells. Previous studies have demonstrated that DcR3 suppresses B cell proliferation in vitro and ameliorates autoimmune diseases in animal models; however, whether and how DcR3 regulates antibody production is unclear. Using a DcR3 transgenic mouse model, we found that DcR3 impaired the T cell-dependent antigen-stimulated antibody response. The number of Ag-specific antibody-secreting cells was transiently reduced, but the concentration of specific antibodies continued to decrease in the DcR3 transgenic mice, implying a direct suppression of antibody production by DcR3. In vitro assays showed that the DcR3-Fc fusion protein attenuated T cell-dependent induced antibody production and reduced the expression of secretory Igh and Xbp1. We found that nuclear factor κB (NF-κB) activity was essential for the expression of Xbp1 in activated B cells. DcR3-Fc attenuated anti-CD40-induced NF-κB activity and Xbp1 promoter activity. Furthermore, DcR3-Fc decreased the expression of Xbp1 in Blimp1+ antibody-secreting cells. Restoration of spliced XBP1 (X-box binding protein 1) in DcR3-treated B cells increased the secretory Ighg1 transcript levels, suggesting that reducing XBP1 is one of the mechanisms by which DcR3 regulates antibody production both in vitro and in vivo. Collectively, these results indicate that in addition to blocking proliferation, DcR3 impairs NF-κB activation, subsequently decreasing the expression of Xbp1, eventually leading to a reduction in antibody secretion.
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Affiliation(s)
- Po-Chun Liu
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Szu-Ying Huang
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, Taipei City, Taiwan
| | - Shie-Liang Hsieh
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei City, Taiwan
- Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Chuen-Miin Leu
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei City, Taiwan
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Yim J, Kim S, Lee HH, Chung JS, Park J. Fragment-based approaches to discover ligands for tumor-specific E3 ligases. Expert Opin Drug Discov 2024; 19:1471-1484. [PMID: 39420586 DOI: 10.1080/17460441.2024.2415310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
INTRODUCTION Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment. AREAS COVERED This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments. EXPERT OPINION Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies.
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Affiliation(s)
- Junhyeong Yim
- Department of Chemistry, Kangwon National University, Chuncheon, Korea
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Korea
| | - Solbi Kim
- Department of Chemistry, Kangwon National University, Chuncheon, Korea
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Korea
| | - Hyung Ho Lee
- Department of Urology, Urological Cancer Center, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Jin Soo Chung
- Department of Urology, Urological Cancer Center, Research Institute and Hospital of National Cancer Center, Goyang, Korea
| | - Jongmin Park
- Department of Chemistry, Kangwon National University, Chuncheon, Korea
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Korea
- Institute for Molecular Science and Fusion Technology, Kangwon National University, Chuncheon, Korea
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8
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Masnikosa R, Cvetković Z, Pirić D. Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review. Int J Mol Sci 2024; 25:11384. [PMID: 39518937 PMCID: PMC11545713 DOI: 10.3390/ijms252111384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 10/13/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies and T-cell engagers, and immune checkpoint inhibitors. Candidate drugs explored in ongoing clinical trials are coupled with diverse toxicity issues and refractoriness to drugs. According to the literature on DLBCL, the promise for new therapeutic targets lies in epigenetic alterations, B-cell receptor and NF-κB pathways. Herein, we present putative targets hiding in lipid pathways, ferroptosis, and the gut microbiome that could be used in addition to immuno-chemotherapy to improve the general health status of DLBCL patients, thus increasing the chance of being cured. It may be time to devote more effort to exploring DLBCL metabolism to discover novel druggable targets. We also performed a bibliometric and knowledge-map analysis of the literature on DLBCL published from 2014-2023.
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Affiliation(s)
- Romana Masnikosa
- Department of Physical Chemistry, Vinca Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia;
| | - Zorica Cvetković
- Department of Hematology, Clinical Hospital Centre Zemun, Vukova 9, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića 8, 11000 Belgrade, Serbia
| | - David Pirić
- Department of Physical Chemistry, Vinca Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia;
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9
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Sarott R, Gourisankar S, Karim B, Nettles S, Yang H, Dwyer BG, Simanauskaite JM, Tse J, Abuzaid H, Krokhotin A, Zhang T, Hinshaw SM, Green MR, Crabtree GR, Gray NS. Relocalizing transcriptional kinases to activate apoptosis. Science 2024; 386:eadl5361. [PMID: 39361741 PMCID: PMC11629774 DOI: 10.1126/science.adl5361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 08/15/2024] [Indexed: 10/05/2024]
Abstract
Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.
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Affiliation(s)
- Roman Sarott
- Department of Chemical and Systems Biology, Stanford University
| | - Sai Gourisankar
- Department of Chemical and Systems Biology, Stanford University
| | - Basel Karim
- Department of Chemistry, Stanford University
| | | | - Haopeng Yang
- Department of Lymphoma-Myeloma, MD Anderson Cancer Center
| | | | | | - Jason Tse
- Department of Chemical and Systems Biology, Stanford University
| | | | | | - Tinghu Zhang
- Department of Chemical and Systems Biology, Stanford University
| | | | | | - Gerald R. Crabtree
- Department of Pathology, Stanford University
- Department Developmental Biology, Stanford University
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10
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Xing Q, Chang D, Xie S, Zhao X, Zhang H, Wang X, Bai X, Dong C. BCL6 is required for the thymic development of TCRαβ +CD8αα + intraepithelial lymphocyte lineage. Sci Immunol 2024; 9:eadk4348. [PMID: 38335269 DOI: 10.1126/sciimmunol.adk4348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/13/2023] [Indexed: 02/12/2024]
Abstract
TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T cells resulted in the near absence of CD8αα+ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα+ αβ IELs and by the majority of thymic PD1+ IELps after agonist selection. Bcl6 deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αβ IELs.
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Affiliation(s)
- Qi Xing
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital, Shanghai 200127, China
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Dehui Chang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Shiyuan Xie
- Institute for Advanced Interdisciplinary Studies and Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Peking University, Beijing 100084, China
| | - Xiaohong Zhao
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Hao Zhang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiaohu Wang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xue Bai
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Chen Dong
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital, Shanghai 200127, China
- Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
- Westlake University School of Medicine-affiliated Hangzhou First Hospital, Hangzhou 310024, China
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11
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Sadeghipour A, Taha SR, Shariat Zadeh M, Kosari F, Babaheidarian P, Fattahi F, Abdi N, Tajik F. Expression and Clinical Significance of Ki-67, CD10, BCL6, MUM1, c-MYC, and EBV in Diffuse Large B Cell Lymphoma Patients. Appl Immunohistochem Mol Morphol 2024; 32:309-321. [PMID: 38872345 DOI: 10.1097/pai.0000000000001208] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/06/2024] [Indexed: 06/15/2024]
Abstract
INTRODUCTION Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in adults. Although studies regarding the association between the expression of Ki-67, CD10, BCL6, and MUM1 proteins, as well as c-MYC amplification and EBV status with clinicopathologic characteristics have rapidly progressed, their co-expression and prognostic role remain unsatisfactory. Therefore, this study aimed to investigate the association between the expression of all markers and clinicopathologic features and their prognostic value in DLBCL. Also, the co-expression of markers was investigated. METHODS The protein expression levels and prognostic significance of Ki-67, CD10, BCL6, and MUM1 were investigated with clinical follow-up in a total of 53 DLBCL specimens (including germinal center B [GCB] and activated B cell [ABC] subtypes) as well as adjacent normal samples using immunohistochemistry (IHC). Besides, the clinical significance and prognostic value of c-MYC and EBV status were also evaluated through chromogenic in situ hybridization (CISH), and their correlation with other markers was also assessed. RESULTS The results demonstrated a positive correlation between CD10 and BCL6 expression, with both markers being associated with the GCB subtype ( P< 0.001 and P =0.001, respectively). Besides, we observe a statistically significant association between MUM1 protein expression and clinicopathologic type ( P< 0.005) as well as a positive association between c-MYC and recurrence ( P =0.028). Our survival analysis showed that patients who had responded to R-CHOP treatment had better overall survival (OS) and progression-free survival (PFS) than those who did not. CONCLUSION Collectively, this study's results add these markers' value to the existing clinical understanding of DLBCL. However, further investigations are needed to explore markers' prognostic and biological roles in DLBCL patients.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Male
- Female
- Middle Aged
- Interferon Regulatory Factors/metabolism
- Interferon Regulatory Factors/genetics
- Proto-Oncogene Proteins c-bcl-6/metabolism
- Proto-Oncogene Proteins c-bcl-6/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- Proto-Oncogene Proteins c-myc/genetics
- Neprilysin/metabolism
- Adult
- Aged
- Ki-67 Antigen/metabolism
- Herpesvirus 4, Human
- Biomarkers, Tumor/metabolism
- Prognosis
- Epstein-Barr Virus Infections
- Aged, 80 and over
- Doxorubicin/therapeutic use
- Immunohistochemistry
- Gene Expression Regulation, Neoplastic
- Vincristine/therapeutic use
- Clinical Relevance
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Affiliation(s)
- Alireza Sadeghipour
- Department of Pathology, School of Medicine, Iran University of Medical Sciences
- Oncopathology Research Center, Iran University of Medical Sciences
| | - Seyed Reza Taha
- Oncopathology Research Center, Iran University of Medical Sciences
| | | | - Farid Kosari
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Pegah Babaheidarian
- Department of Pathology, School of Medicine, Iran University of Medical Sciences
| | - Fahimeh Fattahi
- Clinical Research Development Unit of Ayatollah-Khansari Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Navid Abdi
- Department of Pathology, School of Medicine, Iran University of Medical Sciences
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA
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12
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Gao M, Shi J, Xiao X, Yao Y, Chen X, Wang B, Zhang J. PD-1 regulation in immune homeostasis and immunotherapy. Cancer Lett 2024; 588:216726. [PMID: 38401888 DOI: 10.1016/j.canlet.2024.216726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/31/2024] [Accepted: 02/10/2024] [Indexed: 02/26/2024]
Abstract
Harnessing the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is pivotal in autoimmunity and cancer immunotherapy. PD-1 receptors on immune cells engage with one of its ligands, PD-L1 or PD-L2, expressed on antigen-presenting cells or tumor cells, driving T-cell dysfunction and tumor immune escape. Thus, targeting PD-1/PD-L1 revitalizes cytotoxic T cells for cancer elimination. However, a majority of cancer patients don't respond to PD-1/PD-L1 blockade, and the underlying mechanisms remain partially understood. Recent studies have revealed that PD-1 expression levels or modifications impact the effectiveness of anti-PD-1/PD-L1 treatments. Therefore, understanding the molecular mechanisms governing PD-1 expression and modifications is crucial for innovating therapeutic strategies to enhance the efficacy of PD-1/PD-L1 inhibition. This article presents a comprehensive overview of advancements in PD-1 regulation and highlights their potential in modulating immune homeostasis and cancer immunotherapy, aiming to refine clinical outcomes.
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Affiliation(s)
- Minling Gao
- Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jie Shi
- Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiangling Xiao
- Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yingmeng Yao
- Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xu Chen
- Chongqing University Medical School, Chongqing, 400044, China
| | - Bin Wang
- Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China
| | - Jinfang Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
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13
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Kurata-Sato I, Mughrabi IT, Rana M, Gerber M, Al-Abed Y, Sherry B, Zanos S, Diamond B. Vagus nerve stimulation modulates distinct acetylcholine receptors on B cells and limits the germinal center response. SCIENCE ADVANCES 2024; 10:eadn3760. [PMID: 38669336 PMCID: PMC11051663 DOI: 10.1126/sciadv.adn3760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/26/2024] [Indexed: 04/28/2024]
Abstract
Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4+ T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.
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Affiliation(s)
- Izumi Kurata-Sato
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Ibrahim T. Mughrabi
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Minakshi Rana
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Michael Gerber
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Yousef Al-Abed
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Barbara Sherry
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA
| | - Betty Diamond
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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14
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Cheng YJ, Zhuang Z, Miao YL, Song SS, Bao XB, Yang CH, He JX. Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy. Biochem Pharmacol 2024; 222:116071. [PMID: 38387527 DOI: 10.1016/j.bcp.2024.116071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/26/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Inhibition of the human ubiquitin-specific protease 7 (USP7), the key deubiquitylating enzyme in regulating p53 protein levels, has been considered an attractive anticancer strategy. In order to enhance the cellular activity of FT671, scaffold hopping strategy was employed. This endeavor resulted in the discovery of YCH2823, a novel and potent USP7 inhibitor.YCH2823 demonstrated remarkable efficacy in inhibiting the growth of a specific subset of TP53 wild-type, -mutant, and MYCN-amplified cell lines, surpassing the potency of FT671 by approximately 5-fold. The mechanism of action of YCH2823 involves direct interaction with the catalytic domain of USP7, thereby impeding the cleavage of ubiquitinated substrates. An increase in the expression of p53 and p21, accompanied by G1 phase arrest and apoptosis, was observed upon treatment with YCH2823. Subsequently, the knockdown of p53 or p21 in CHP-212 cells exhibited a substantial reduction in sensitivity to YCH2823, as evidenced by a considerable increase in IC50 values up to 690-fold. Furthermore, YCH2823 treatment specifically enhanced the transcriptional and protein levels of BCL6 in sensitive cells. Moreover, a synergistic effect between USP7 inhibitors and mTOR inhibitors was observed, suggesting the possibility of novel therapeutic strategies for cancer treatment. In conclusion, YCH2823 exhibits potential as an anticancer agent for the treatment of both TP53 wild-type and -mutant tumors.
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Affiliation(s)
- Yong-Jun Cheng
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046 China
| | - Zhen Zhuang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Yu-Ling Miao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Shan-Shan Song
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Xu-Bin Bao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
| | - Chun-Hao Yang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
| | - Jin-Xue He
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Avenue, Nanjing 210046 China.
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15
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Koshkin A, Herbach U, Martínez MR, Gandrillon O, Crauste F. Stochastic modeling of a gene regulatory network driving B cell development in germinal centers. PLoS One 2024; 19:e0301022. [PMID: 38547073 PMCID: PMC10977792 DOI: 10.1371/journal.pone.0301022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 03/08/2024] [Indexed: 04/02/2024] Open
Abstract
Germinal centers (GCs) are the key histological structures of the adaptive immune system, responsible for the development and selection of B cells producing high-affinity antibodies against antigens. Due to their level of complexity, unexpected malfunctioning may lead to a range of pathologies, including various malignant formations. One promising way to improve the understanding of malignant transformation is to study the underlying gene regulatory networks (GRNs) associated with cell development and differentiation. Evaluation and inference of the GRN structure from gene expression data is a challenging task in systems biology: recent achievements in single-cell (SC) transcriptomics allow the generation of SC gene expression data, which can be used to sharpen the knowledge on GRN structure. In order to understand whether a particular network of three key gene regulators (BCL6, IRF4, BLIMP1), influenced by two external stimuli signals (surface receptors BCR and CD40), is able to describe GC B cell differentiation, we used a stochastic model to fit SC transcriptomic data from a human lymphoid organ dataset. The model is defined mathematically as a piecewise-deterministic Markov process. We showed that after parameter tuning, the model qualitatively recapitulates mRNA distributions corresponding to GC and plasmablast stages of B cell differentiation. Thus, the model can assist in validating the GRN structure and, in the future, could lead to better understanding of the different types of dysfunction of the regulatory mechanisms.
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Affiliation(s)
- Alexey Koshkin
- Inria Dracula, Villeurbanne, France
- Laboratory of Biology and Modelling of the Cell, Universite de Lyon, ENS de Lyon, Université Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France
| | - Ulysse Herbach
- Université de Lorraine, CNRS, Inria, IECL, Nancy, France
| | | | - Olivier Gandrillon
- Inria Dracula, Villeurbanne, France
- Laboratory of Biology and Modelling of the Cell, Universite de Lyon, ENS de Lyon, Université Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France
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16
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Iborra-Pernichi M, Ruiz García J, Velasco de la Esperanza M, Estrada BS, Bovolenta ER, Cifuentes C, Prieto Carro C, González Martínez T, García-Consuegra J, Rey-Stolle MF, Rupérez FJ, Guerra Rodriguez M, Argüello RJ, Cogliati S, Martín-Belmonte F, Martínez-Martín N. Defective mitochondria remodelling in B cells leads to an aged immune response. Nat Commun 2024; 15:2569. [PMID: 38519473 PMCID: PMC10960012 DOI: 10.1038/s41467-024-46763-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/08/2024] [Indexed: 03/25/2024] Open
Abstract
The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.
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Affiliation(s)
- Marta Iborra-Pernichi
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Jonathan Ruiz García
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - María Velasco de la Esperanza
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Belén S Estrada
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Elena R Bovolenta
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Claudia Cifuentes
- Program of Interactions with the Environment, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Cristina Prieto Carro
- Program of Interactions with the Environment, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Tamara González Martínez
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - José García-Consuegra
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - María Fernanda Rey-Stolle
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain
| | - Francisco Javier Rupérez
- Centre for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain
| | - Milagros Guerra Rodriguez
- Electron Microscopy Facility, Centro de Biología Molecular "Severo Ochoa, " Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Rafael J Argüello
- Aix Marseille Univ, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Sara Cogliati
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Fernando Martín-Belmonte
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Nuria Martínez-Martín
- Program of Tissue and Organ Homeostasis, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
- Intestinal Morphogenesis and Homeostasis Group, Area 3-Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
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17
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Cao H, Naik SH, Amann-Zalcenstein D, Hickey P, Salim A, Cao B, Nilsson SK, Keightley MC, Lieschke GJ. Late fetal hematopoietic failure results from ZBTB11 deficiency despite abundant HSC specification. Blood Adv 2023; 7:6506-6519. [PMID: 37567157 PMCID: PMC10632610 DOI: 10.1182/bloodadvances.2022009580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
Hematopoiesis produces diverse blood cell lineages to meet the basal needs and sudden demands of injury or infection. A rapid response to such challenges requires the expansion of specific lineages and a prompt return to balanced steady-state levels, necessitating tightly coordinated regulation. Previously we identified a requirement for the zinc finger and broad complex, tramtrak, bric-a-brac domain-containing 11 (ZBTB11) transcription factor in definitive hematopoiesis using a forward genetic screen for zebrafish myeloid mutants. To understand its relevance to mammalian systems, we extended these studies to mice. When Zbtb11 was deleted in the hematopoietic compartment, embryos died at embryonic day (E) 18.5 with hematopoietic failure. Zbtb11 hematopoietic knockout (Zbtb11hKO) hematopoietic stem cells (HSCs) were overabundantly specified from E14.5 to E17.5 compared with those in controls. Overspecification was accompanied by loss of stemness, inability to differentiate into committed progenitors and mature lineages in the fetal liver, failure to seed fetal bone marrow, and total hematopoietic failure. The Zbtb11hKO HSCs did not proliferate in vitro and were constrained in cell cycle progression, demonstrating the cell-intrinsic role of Zbtb11 in proliferation and cell cycle regulation in mammalian HSCs. Single-cell RNA sequencing analysis identified that Zbtb11-deficient HSCs were underrepresented in an erythroid-primed subpopulation and showed downregulation of oxidative phosphorylation pathways and dysregulation of genes associated with the hematopoietic niche. We identified a cell-intrinsic requirement for Zbtb11-mediated gene regulatory networks in sustaining a pool of maturation-capable HSCs and progenitor cells.
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Affiliation(s)
- Huimin Cao
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
- Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC, Australia
| | - Shalin H. Naik
- Department of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Single Cell Open Research Endeavour, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Daniela Amann-Zalcenstein
- Single Cell Open Research Endeavour, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
- Advanced Genomics Facility, Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Peter Hickey
- Single Cell Open Research Endeavour, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
- Advanced Genomics Facility, Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Agus Salim
- Mathematics and Statistics, La Trobe University, Bundoora, VIC, Australia
- Melbourne School of Population and Global Health, School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia
| | - Benjamin Cao
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
- Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC, Australia
| | - Susan K. Nilsson
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
- Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC, Australia
| | - M. Cristina Keightley
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia
- Rural Clinical Sciences, La Trobe Rural Health School, Bendigo, VIC, Australia
| | - Graham J. Lieschke
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
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18
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Sarott R, Gourisankar S, Karim B, Nettles S, Yang H, Dwyer BG, Simanauskaite JM, Tse J, Abuzaid H, Krokhotin A, Zhang T, Hinshaw SM, Green MR, Crabtree GR, Gray NS. Borrowing Transcriptional Kinases to Activate Apoptosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.23.563687. [PMID: 37961702 PMCID: PMC10634765 DOI: 10.1101/2023.10.23.563687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.
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19
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Shehata L, Thouvenel CD, Hondowicz BD, Pew LA, Rawlings DJ, Choi J, Pepper M. IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.26.525749. [PMID: 36747852 PMCID: PMC9900890 DOI: 10.1101/2023.01.26.525749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. Here, we show that IL-4 signaling in GC B cells directly downregulates BCL6 via negative autoregulation to release cells from the GC program and promote MBC formation. This selection event requires additional survival cues and can therefore result in either GC exit or death. We demonstrate that both increasing IL-4 bioavailability or limiting IL-4 signaling disrupt MBC selection stringency. In this way, IL-4 control of BCL6 expression serves as a tunable switch within the GC to tightly regulate MBC selection and affinity maturation.
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20
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Petersone L, Wang CJ, Edner NM, Fabri A, Nikou SA, Hinze C, Ross EM, Ntavli E, Elfaki Y, Heuts F, Ovcinnikovs V, Rueda Gonzalez A, Houghton LP, Li HM, Zhang Y, Toellner KM, Walker LSK. IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation. J Exp Med 2023; 220:e20221653. [PMID: 37466652 PMCID: PMC10355162 DOI: 10.1084/jem.20221653] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 05/06/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023] Open
Abstract
Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.
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Affiliation(s)
- Lina Petersone
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Chun Jing Wang
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Natalie M Edner
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Astrid Fabri
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Spyridoula-Angeliki Nikou
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Claudia Hinze
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Ellen M Ross
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Elisavet Ntavli
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Yassin Elfaki
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Frank Heuts
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Vitalijs Ovcinnikovs
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Andrea Rueda Gonzalez
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Luke P Houghton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Hannah M Li
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
| | - Yang Zhang
- Institute of Immunology and Immunotherapy, University of Birmingham , Birmingham, UK
| | - Kai-Michael Toellner
- Institute of Immunology and Immunotherapy, University of Birmingham , Birmingham, UK
| | - Lucy S K Walker
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London , London, UK
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21
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Schips M, Mitra T, Bandyopadhyay A, Meyer-Hermann M. Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres. Front Immunol 2023; 14:1253704. [PMID: 37818361 PMCID: PMC10561256 DOI: 10.3389/fimmu.2023.1253704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/29/2023] [Indexed: 10/12/2023] Open
Abstract
The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s-ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s-ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.
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Affiliation(s)
- Marta Schips
- Department of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, Germany
| | - Tanmay Mitra
- Department of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, Germany
| | - Arnab Bandyopadhyay
- Department of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, Germany
| | - Michael Meyer-Hermann
- Department of Systems Immunology, Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZI), Braunschweig, Germany
- Institut für Biochemie, Biotechnologie und Bioinformatik, Technische Universitat Braunschweig, Braunschweig, Germany
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22
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Koehrer S, Burger JA. Chronic Lymphocytic Leukemia: Disease Biology. Acta Haematol 2023; 147:8-21. [PMID: 37717577 PMCID: PMC11753505 DOI: 10.1159/000533610] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 08/13/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and generally induce durable remissions in CLL patients, even in patients with high-risk disease. By disrupting tissue homing receptor (i.e., chemokine receptor and adhesion molecule) signaling, these kinase inhibitors also mobilize CLL cells from the lymphatic tissues into the peripheral blood (PB), causing a transient redistribution lymphocytosis, thereby depriving CLL cells from nurturing factors within the tissue niches. SUMMARY The clinical success of the BTK inhibitors in CLL underscores the central importance of the BCR in CLL pathogenesis. Here, we review CLL pathogenesis with a focus on the role of the BCR and other microenvironment cues. KEY MESSAGES (i) CLL cells rely on signals from their microenvironment for proliferation and survival. (ii) These signals are mediated by the BCR as well as chemokine and integrin receptors and their respective ligands. (iii) Targeting the CLL/microenvironment interaction with small-molecule inhibitors provides a highly effective treatment strategy, even in high-risk patients.
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Affiliation(s)
- Stefan Koehrer
- Department of Laboratory Medicine, Klinik Donaustadt, Vienna, Austria
- Labdia Labordiagnostik, Clinical Genetics, Vienna, Austria
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Jan A. Burger
- Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
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23
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Phelan JD, Staudt LM. Double-headed molecule activates cell-death pathways in cancer cells. Nature 2023:10.1038/d41586-023-02213-4. [PMID: 37495782 DOI: 10.1038/d41586-023-02213-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
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24
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Hoppe MM, Jaynes P, Shuangyi F, Peng Y, Sridhar S, Hoang PM, Liu CX, De Mel S, Poon L, Chan EHL, Lee J, Ong CK, Tang T, Lim ST, Nagarajan C, Grigoropoulos NF, Tan SY, Hue SSS, Chang ST, Chuang SS, Li S, Khoury JD, Choi H, Harris C, Bottos A, Gay LJ, Runge HF, Moutsopoulos I, Mohorianu I, Hodson DJ, Farinha P, Mottok A, Scott DW, Pitt JJ, Chen J, Kumar G, Kannan K, Chng WJ, Chee YL, Ng SB, Tripodo C, Jeyasekharan AD. Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma. Cancer Discov 2023; 13:1144-1163. [PMID: 37071673 PMCID: PMC10157367 DOI: 10.1158/2159-8290.cd-22-0998] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/29/2022] [Accepted: 02/13/2023] [Indexed: 04/19/2023]
Abstract
Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.
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Affiliation(s)
- Michal Marek Hoppe
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Patrick Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Fan Shuangyi
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yanfen Peng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Shruti Sridhar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Phuong Mai Hoang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Clementine Xin Liu
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
| | - Sanjay De Mel
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Limei Poon
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Esther Hian Li Chan
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Joanne Lee
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Choon Kiat Ong
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Tiffany Tang
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Soon Thye Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | | | - Soo-Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Susan Swee-Shan Hue
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Sheng-Tsung Chang
- Department of Pathology, Chi-Mei Medical Center, Tainan City, Taiwan
| | - Shih-Sung Chuang
- Department of Pathology, Chi-Mei Medical Center, Tainan City, Taiwan
| | - Shaoying Li
- Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joseph D. Khoury
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Hyungwon Choi
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Carl Harris
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Laura J. Gay
- Wellcome MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
| | | | | | - Irina Mohorianu
- Wellcome MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
| | - Daniel J. Hodson
- Wellcome MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
| | | | - Anja Mottok
- BC Cancer Research Centre, Vancouver, Canada
| | | | - Jason J. Pitt
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Jinmiao Chen
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore
| | - Gayatri Kumar
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kasthuri Kannan
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wee Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yen Lin Chee
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Siok-Bian Ng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Claudio Tripodo
- Tumor Immunology Unit, University of Palermo, Palermo, Italy
- IFOM ETS – The AIRC Institute of Molecular Oncology, Milan, Italy
| | - Anand D. Jeyasekharan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Health System, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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25
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Ekemen S, Comunoglu C, Kayhan CK, Bilir E, Cavusoglu I, Etiler N, Bilgi S, Ince U, Coban C, Erden HF. Endometrial Staining of CD56 (Uterine Natural Killer), BCL-6, and CD138 (Plasma Cells) Improve Diagnosis and Clinical Pregnancy Outcomes in Unexplained Infertility and Recurrent IVF Failures: Standardization of Diagnosis with Digital Pathology. Diagnostics (Basel) 2023; 13:diagnostics13091557. [PMID: 37174948 PMCID: PMC10177933 DOI: 10.3390/diagnostics13091557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
In women with unexplained infertility (UI) and recurrent in vitro fertilization (IVF) failures, the etiology is often unclear. Endometrial immune perturbations and the use of immune markers associated with these dysregulations are of great interest in the diagnosis and treatment of UI. However, reliable biomarkers and standardized quantification methods are lacking. Here, to address endometrial immune dysregulation in UI patients with recurrent IVF failures, we performed endometrial tissue sampling and immunostaining of CD56 (uNK), CD138, and BCL-6. Of these cases, 57.9% had positive CD56 in the endometrial stroma, while 46.1% had positive BCL-6 in the glandular epithelium, and 14.5% of the cases were found to be positive for CD138. Combined staining rates were 60.5%, 68.4%, and 71.05% for (CD56 or BCL-6), (CD56 or CD138), and (CD56, BCL-6, or CD138), respectively. There was a significant correlation between CD56 and BCL-6 positivity, while CD138 positivity was an independent parameter. After the recommended targeted therapy, pregnancy rates were found to increase from 58.5% to 61.6% and 73.8% in CD56-positive, (CD56- or BCL-6-positive), and (CD56-, BCL-6-, or CD138-positive) cases, respectively. Notably, a retrospective evaluation of digital pathology and light microscopy results showed a significant correlation. This study suggests that the examination of CD56, BCL-6, and CD138 in the same endometrial sample may be an effective method in determining the etiology of UI and reaching an early diagnosis and treatment options. Moreover, digital pathology can be used in the evaluation of CD56 and BCL-6 to provide objective, rapid, and reliable results.
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Affiliation(s)
- Suheyla Ekemen
- Vocational School of Health Services, Kerem Aydınlar Campus, Acıbadem University, Istanbul 34752, Turkey
- Acibadem Central Pathology Laboratory, Kerem Aydinlar Campus, Istanbul 34752, Turkey
| | - Cem Comunoglu
- Department of Pathology, Dr. Cemil Tascioglu City Hospital, University of Health Sciences, Istanbul 34668, Turkey
| | - Cavit Kerem Kayhan
- Acibadem Central Pathology Laboratory, Kerem Aydinlar Campus, Istanbul 34752, Turkey
| | - Ebru Bilir
- School of Medicine, Bahcesehir University, Istanbul 34349, Turkey
| | - Ilkay Cavusoglu
- Women's Health and Gynecological Nursing, Institute of Health Sciences, Biruni University, Istanbul 34010, Turkey
| | - Nilay Etiler
- Department of Public Health, School of Medicine, Istanbul Okan University, Istanbul 34947, Turkey
- Public Health Department, University of Nevada, Reno, NV 89509, USA
| | - Selcuk Bilgi
- Acibadem Central Pathology Laboratory, Kerem Aydinlar Campus, Istanbul 34752, Turkey
| | - Umit Ince
- Acibadem Central Pathology Laboratory, Kerem Aydinlar Campus, Istanbul 34752, Turkey
- Department of Digital Pathology, School of Medicine, Acıbadem University, Istanbul 34752, Turkey
| | - Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, Institute of Medical Science (IMSUT), University of Tokyo, Tokyo 108-8639, Japan
| | - Halit Firat Erden
- Obstetrics and Gynecology Infertility Clinic, Zorlu Center, Istanbul 34340, Turkey
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26
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Yang S, Nie T, She H, Tao K, Lu F, Hu Y, Huang L, Zhu L, Feng D, He D, Qi J, Kukar T, Ma L, Mao Z, Yang Q. Regulation of TFEB nuclear localization by HSP90AA1 promotes autophagy and longevity. Autophagy 2023; 19:822-838. [PMID: 35941759 PMCID: PMC9980472 DOI: 10.1080/15548627.2022.2105561] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/02/2022] Open
Abstract
TFEB (transcription factor EB) regulates multiple genes involved in the process of macroautophagy/autophagy and plays a critical role in lifespan determination. However, the detailed mechanisms that regulate TFEB activity are not fully clear. In this study, we identified a role for HSP90AA1 in modulating TFEB. HSP90AA1 was phosphorylated by CDK5 at Ser 595 under basal condition. This phosphorylation inhibited HSP90AA1, disrupted its binding to TFEB, and impeded TFEB's nuclear localization and subsequent autophagy induction. Pro-autophagy signaling attenuated CDK5 activity and enhanced TFEB function in an HSP90AA1-dependent manner. Inhibition of HSP90AA1 function or decrease in its expression significantly attenuated TFEB's nuclear localization and transcriptional function following autophagy induction. HSP90AA1-mediated regulation of a TFEB ortholog was involved in the extended lifespan of Caenorhabditis elegans in the absence of its food source bacteria. Collectively, these findings reveal that this regulatory process plays an important role in modulation of TFEB, autophagy, and longevity.Abbreviations : AL: autolysosome; AP: autophagosome; ATG: autophagy related; BafA1: bafilomycin A1; CDK5: cyclin-dependent kinase 5; CDK5R1: cyclin dependent kinase 5 regulatory subunit 1; CR: calorie restriction; FUDR: 5-fluorodeoxyuridine; HSP90AA1: heat shock protein 90 alpha family class A member 1; MAP1LC3: microtubule associated protein 1 light chain 3; NB: novobiocin sodium; SQSTM1: sequestosome 1; TFEB: transcription factor EB; WT: wild type.
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Affiliation(s)
- Shaosong Yang
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Tiejian Nie
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Hua She
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Kai Tao
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Fangfang Lu
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yiman Hu
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Lu Huang
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Lin Zhu
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Dayun Feng
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Dan He
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jing Qi
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Thomas Kukar
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Long Ma
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Zixu Mao
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Qian Yang
- Department of Experimental Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
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Flümann R, Hansen J, Pelzer BW, Nieper P, Lohmann T, Kisis I, Riet T, Kohlhas V, Nguyen PH, Peifer M, Abedpour N, Bosco G, Thomas RK, Kochanek M, Knüfer J, Jonigkeit L, Beleggia F, Holzem A, Büttner R, Lohneis P, Meinel J, Ortmann M, Persigehl T, Hallek M, Calado DP, Chmielewski M, Klein S, Göthert JR, Chapuy B, Zevnik B, Wunderlich FT, von Tresckow B, Jachimowicz RD, Melnick AM, Reinhardt HC, Knittel G. Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies. Blood Cancer Discov 2023; 4:78-97. [PMID: 36346827 PMCID: PMC9816818 DOI: 10.1158/2643-3230.bcd-22-0007] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 10/06/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022] Open
Abstract
Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell-specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo. SIGNIFICANCE Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non-GCB-DLBCL patients. See related commentary by Leveille et al., p. 8. This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Ruth Flümann
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Julia Hansen
- Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Benedikt W. Pelzer
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York
| | - Pascal Nieper
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Tim Lohmann
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Ilmars Kisis
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Tobias Riet
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Viktoria Kohlhas
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Phuong-Hien Nguyen
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Martin Peifer
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Nima Abedpour
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Graziella Bosco
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Roman K. Thomas
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Moritz Kochanek
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Jacqueline Knüfer
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Lorenz Jonigkeit
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Filippo Beleggia
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Department of Translational Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Alessandra Holzem
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Philipp Lohneis
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Jörn Meinel
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Monika Ortmann
- Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Thorsten Persigehl
- Department of Radiology and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Michael Hallek
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | | | - Markus Chmielewski
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Sebastian Klein
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany
| | - Joachim R. Göthert
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany
| | - Bjoern Chapuy
- Department of Hematology, Oncology and Tumorimmunology, Charité, University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Branko Zevnik
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - F. Thomas Wunderlich
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Bastian von Tresckow
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany
| | - Ron D. Jachimowicz
- Department I of Internal Medicine, Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Ari M. Melnick
- Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York
| | - Hans Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany
| | - Gero Knittel
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, West German Cancer Center, German Cancer Consortium (DKTK partner site Essen), Center for Molecular Biotechnology, Essen, Germany
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Gu H, He J, Li Y, Mi D, Guan T, Guo W, Liu B, Chen Y. B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas. J Med Chem 2022; 65:15559-15583. [PMID: 36441945 DOI: 10.1021/acs.jmedchem.2c01433] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.
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Affiliation(s)
- Haijun Gu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jia He
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yuzhan Li
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Dazhao Mi
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Tian Guan
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Weikai Guo
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Bo Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yihua Chen
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
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Garcia B, Dong F, Casadei E, Rességuier J, Ma J, Cain KD, Castrillo PA, Xu Z, Salinas I. A Novel Organized Nasopharynx-Associated Lymphoid Tissue in Teleosts That Expresses Molecular Markers Characteristic of Mammalian Germinal Centers. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2215-2226. [PMID: 36426979 DOI: 10.4049/jimmunol.2200396] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/16/2022] [Indexed: 01/04/2023]
Abstract
Nasal immunity is an ancient and conserved arm of the mucosal immune system in vertebrates. In teleost fish, we previously reported the presence of a nasopharynx-associated lymphoid tissue (NALT) characterized by scattered immune cells located in the trout olfactory lamellae. This diffuse NALT mounts innate and adaptive immune responses to nasal infection or vaccination. In mammals, lymphoid structures such as adenoids and tonsils support affinity maturation of the adaptive immune response in the nasopharyngeal cavity. These structures, known as organized NALT (O-NALT), have not been identified in teleost fish to date, but their evolutionary forerunners exist in sarcopterygian fish. In this study, we report that the rainbow trout nasal cavity is lined with a lymphoepithelium that extends from the most dorsal opening of the nares to the ventral nasal cavity. Within the nasal lymphoepithelium we found lymphocyte aggregates called O-NALT in this study that are composed of ∼ 56% CD4+, 24% IgM+, 16% CD8α+, and 4% IgT+ lymphocytes and that have high constitutive aicda mRNA expression. Intranasal (i.n.) vaccination with live attenuated infectious hematopoietic necrosis virus triggers expansions of B and T cells and aicda expression in response to primary i.n. vaccination. IgM+ B cells undergo proliferation and apoptosis within O-NALT upon prime but not boost i.n. vaccination. Our results suggest that novel mucosal microenvironments such as O-NALT may be involved in the affinity maturation of the adaptive immune response in early vertebrates.
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Affiliation(s)
- Benjamin Garcia
- Department of Biology, Center for Evolutionary and Theoretical Immunology, University of New Mexico, Albuquerque, NM
| | - Fen Dong
- Department of Biology, Center for Evolutionary and Theoretical Immunology, University of New Mexico, Albuquerque, NM.,Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, China
| | - Elisa Casadei
- Department of Biology, Center for Evolutionary and Theoretical Immunology, University of New Mexico, Albuquerque, NM
| | - Julien Rességuier
- Section for Physiology and Cell Biology, Department of Biosciences, University of Oslo, Oslo, Norway
| | - Jie Ma
- Department of Fish and Wildlife Sciences, University of Idaho, Moscow, ID; and
| | - Kenneth D Cain
- Department of Fish and Wildlife Sciences, University of Idaho, Moscow, ID; and
| | - Pedro A Castrillo
- Department of Biology, Center for Evolutionary and Theoretical Immunology, University of New Mexico, Albuquerque, NM.,Departamento de Anatomía, Producción Animal y Ciencias Clínicas Veterinarias, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Zhen Xu
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, China
| | - Irene Salinas
- Department of Biology, Center for Evolutionary and Theoretical Immunology, University of New Mexico, Albuquerque, NM
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Advances in Understanding of Metabolism of B-Cell Lymphoma: Implications for Therapy. Cancers (Basel) 2022; 14:cancers14225552. [PMID: 36428647 PMCID: PMC9688663 DOI: 10.3390/cancers14225552] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
There have been significant recent advances in the understanding of the role of metabolism in normal and malignant B-cell biology. Previous research has focused on the role of MYC and mammalian target of rapamycin (mTOR) and how these interact with B-cell receptor signaling and hypoxia to regulate glycolysis, glutaminolysis, oxidative phosphorylation (OXPHOS) and related metabolic pathways in germinal centers. Many of the commonest forms of lymphoma arise from germinal center B-cells, reflecting the physiological attenuation of normal DNA damage checkpoints to facilitate somatic hypermutation of the immunoglobulin genes. As a result, these lymphomas can inherit the metabolic state of their cell-of-origin. There is increasing interest in the potential of targeting metabolic pathways for anti-cancer therapy. Some metabolic inhibitors such as methotrexate have been used to treat lymphoma for decades, with several new agents being recently licensed such as inhibitors of phosphoinositide-3-kinase. Several other inhibitors are in development including those blocking mTOR, glutaminase, OXPHOS and monocarboxylate transporters. In addition, recent work has highlighted the importance of the interaction between diet and cancer, with particular focus on dietary modifications that restrict carbohydrates and specific amino acids. This article will review the current state of this field and discuss future developments.
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Quach HT, Hou Z, Bellis RY, Saini JK, Amador-Molina A, Adusumilli PS, Xiong Y. Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1. Expert Opin Investig Drugs 2022; 31:1187-1202. [PMID: 36448335 PMCID: PMC10085570 DOI: 10.1080/13543784.2022.2152323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 11/23/2022] [Indexed: 12/05/2022]
Abstract
INTRODUCTION In solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor β (TGFβ) in diverse immunity is well-established; however, systemic blockade of TGFβ is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGFβ and PD-1/PD-L1 pathways. AREAS COVERED We focus on TGFβ and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGFβ in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGFβ and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies. EXPERT OPINION The heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGFβ and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGFβ in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.
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Affiliation(s)
- Hue Tu Quach
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Zhaohua Hou
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Rebecca Y. Bellis
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Jasmeen K. Saini
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Alfredo Amador-Molina
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Prasad S. Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Director, Mesothelioma Program; Head, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Yuquan Xiong
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
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Legorreta-Haquet MV, Santana-Sánchez P, Chávez-Sánchez L, Chávez-Rueda AK. The effect of prolactin on immune cell subsets involved in SLE pathogenesis. Front Immunol 2022; 13:1016427. [PMID: 36389803 PMCID: PMC9650038 DOI: 10.3389/fimmu.2022.1016427] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/13/2022] [Indexed: 08/27/2023] Open
Abstract
The higher frequency of autoimmune diseases in the female population compared to males suggests that certain hormones, such as prolactin (PRL), play a role in determining the prevalence of autoimmunity in women, particularly during childbearing age. PRL can act not only as a hormone but also as a cytokine, being able to modulate immune responses. Hyperprolactinemia has been implicated in the pathogenesis of various autoimmune diseases where it may affect disease activity. One of the conditions where PRL has such a role is systemic lupus erythematosus (SLE). PRL regulates the proliferation and survival of both lymphoid and myeloid cells. It also affects the selection of T-cell repertoires by influencing the thymic microenvironment. In autoimmune conditions, PRL interferes with the activity of regulatory T cells. It also influences B cell tolerance by lowering the activation threshold of anergic B cells. The production of CD40L and cytokines, such as interleukin IL-6, are also promoted by PRL. This, in turn, leads to the production of autoantibodies, one of the hallmarks of SLE. PRL increases the cytotoxic activity of T lymphocytes and the secretion of proinflammatory cytokines. The production of proinflammatory cytokines, particularly those belonging to the type 1 interferon (IFN) family, is part of the SLE characteristic genetic signature. PRL also participates in the maturation and differentiation of dendritic cells, promoting the presentation of autoantigens and high IFNα secretion. It also affects neutrophil function and the production of neutrophil traps. Macrophages and dendritic cells can also be affected by PRL, linking this molecule to the abnormal behavior of both innate and adaptive immune responses.This review aimed to highlight the importance of PRL and its actions on the cells of innate and adaptive immune responses. Additionally, by elucidating the role of PRL in SLE etiopathogenesis, this work will contribute to a better understanding of the factors involved in SLE development and regulation.
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Affiliation(s)
| | | | | | - Adriana Karina Chávez-Rueda
- Unidad de Investigación Médica en Inmunología (UIM) en Inmunología, Hospital de Pediatría, Centro Médico Nacional (CMN) Siglo XXI, Instituto Mexicano del Seguro Social, México City, Mexico
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Tanner L, Bergwik J, Bhongir RKV, Pan L, Dong C, Wallner O, Kalderén C, Helleday T, Boldogh I, Adner M, Egesten A. Pharmacological OGG1 inhibition decreases murine allergic airway inflammation. Front Pharmacol 2022; 13:999180. [PMID: 36324676 PMCID: PMC9619105 DOI: 10.3389/fphar.2022.999180] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 10/05/2022] [Indexed: 12/01/2022] Open
Abstract
Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2 T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation. Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histological analyses and immunofluorescent staining were used to confirm immune cell influx and goblet cell hyperplasia of the airways. A PCR array was used to assess asthma-related genes in murine lung tissue following TH5487 treatment. Finally, airway hyperresponsiveness was determined using in vivo lung function measurement. Results: In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-κB and expression of proinflammatory cytokines and chemokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed differences in several important regulators, including down regulation of Tnfrsf4, Arg1, Ccl12 and Ccl11, and upregulation of the negative regulator of type 2 inflammation, Bcl6. Furthermore, the gene Clca1 was upregulated following TH5487 treatment, which should be explored further due to its ambiguous role in allergic asthma. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Conclusion: Taken together, the data presented in this study suggest OGG1 as a clinically relevant pharmacological target for the treatment of allergic inflammation.
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Affiliation(s)
- Lloyd Tanner
- Department of Clinical Sciences Lund, Respiratory Medicine, Allergology, and Palliative Medicine, Lund University and Skåne University Hospital, Lund, Sweden
- *Correspondence: Lloyd Tanner,
| | - Jesper Bergwik
- Department of Clinical Sciences Lund, Respiratory Medicine, Allergology, and Palliative Medicine, Lund University and Skåne University Hospital, Lund, Sweden
| | - Ravi K. V. Bhongir
- Department of Clinical Sciences Lund, Respiratory Medicine, Allergology, and Palliative Medicine, Lund University and Skåne University Hospital, Lund, Sweden
| | - Lang Pan
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, United States
| | - Caijuan Dong
- Unit of Experimental Asthma and Allergy Research, Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden
| | - Olov Wallner
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Christina Kalderén
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Oxcia AB, Stockholm, Sweden
| | - Thomas Helleday
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Oxcia AB, Stockholm, Sweden
- Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Istvan Boldogh
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, United States
| | - Mikael Adner
- Unit of Experimental Asthma and Allergy Research, Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden
| | - Arne Egesten
- Department of Clinical Sciences Lund, Respiratory Medicine, Allergology, and Palliative Medicine, Lund University and Skåne University Hospital, Lund, Sweden
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Zhu Y, Lei C, Jiang Q, Yu Q, Qiu L. DSF/Cu induces antitumor effect against diffuse large B-cell lymphoma through suppressing NF-κB/BCL6 pathways. Cancer Cell Int 2022; 22:236. [PMID: 35883106 PMCID: PMC9317061 DOI: 10.1186/s12935-022-02661-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Background The B-cell lymphoma 6 (BCL6) oncogene is required for the survival of diffuse large B-cell lymphoma (DLBCL), which is incurable using conventional chemotherapy. Thus, it is imperative to improve the survival of patients with DLBCL. Disulfide (DSF) has been shown to have anticancer effects, but its effect on DLBCL remains unclear. Methods Four DLBCL cell lines (OCI-LY1, OCI-LY7, OCI-LY10 and U2932) and primary DLBCL cells from eight newly diagnosed DLBCL patients were pretreated with DSF alone or in combination with Cu. Cell morphology was observed under microscope. Flow cytometry was performed to evaluate the cell apoptosis, cell cycle, the mitochondrial membrane potential and the intracellular accumulation of reactive oxygen species (ROS). The protein expression was respectively measured by flow cytometry and western blotting. Results DSF or DSF/Cu exhibited a marked inhibitory effect on the growth of DLBCL cells, accompanied by cell cycle arrest at the G0/G1 phase. Meanwhile, DSF or DSF/Cu significantly induced DLBCL cells apoptosis. Further study revealed that DSF or DSF/Cu promoted apoptosis by inhibiting NF-κB signaling pathway. Interestingly, DSF/Cu significantly reduced BCL6 and AIP levels. In addition, DSF significantly up-regulate p53 protein in OCI-LY7 and OCI-LY10 while down-regulate p53 protein in OCI-LY1 and U2932. Conclusion These results provided evidence for the anti-lymphoma effects of DSF on DLBCL and suggested that DSF has therapeutic potential to DLBCL. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02661-4.
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Affiliation(s)
- Yunying Zhu
- Department of Clinical Laboratory, College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou, 310014, Zhejiang, China.,Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Chenshuang Lei
- Department of Clinical Laboratory, College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou, 310014, Zhejiang, China.,Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Qian Jiang
- Department of Clinical Laboratory, College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou, 310014, Zhejiang, China.,Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Qinhua Yu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China
| | - Liannv Qiu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), 158 Shangtang Road, Hangzhou, 310014, Zhejiang, China.
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[Large B-cell lymphoma with IRF4 rearrangement: six case reports and a literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:475-480. [PMID: 35968590 PMCID: PMC9800220 DOI: 10.3760/cma.j.issn.0253-2727.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Objective: To study the clinical, histopathological, and genetic features of large B-cell lymphoma (LBCL) with IRF4 rearrangement. Methods: Six patients presenting at our center between December 2017 and October 2021 were evaluated by pathological examination, fluorescence in situ hybridization, and next-generation sequencing. The relevant literature was reviewed. Results: ①The study sample included three males and three females with a median age of 33 years. Three tumors were in the tonsils, two in the lymphoid nodes, and one in the dorsal lump. All patients were treated using the RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) regimen. All of them were alive at the time of follow-up in November 2021. ②Microscopic examination showed an entirely follicular pattern in one case and an entirely diffused pattern in 5 cases. The tumor cells were medium to large, and most of the lesions were dilatative with brisk mitotic activity (n=five cases) and no starry sky pattern (n=6 cases) . ③Four cases exhibited a GCB phenotype, and the other two exhibited a non-GCB phenotype. All of the cases were positive for CD20, PAX-5, MUM, and BCL6, and negative for CD5. Moreover, CD10, BCL2, and c-MYC were positive in 4, 3, and 2 cases, respectively.④IRF4 gene rearrangement was identified in all cases, BCL6 gene rearrangement was detected in 5 cases, and 2 cases were positive. BCL2 and MYC gene rearrangement were performed in 5 cases, all negative. ⑤Three paraffin tissue samples were used for next-generation sequencing, and lymphoma-related gene mutations such as IRF4, TP53, IGLL5, and MYD88 were detected in 3 cases. Conclusions: LBCL with IRF4 rearrangement is a rare entity with unique clinical, pathological, and genetic characteristics. This entity's pathogenesis, treatment options, and long-term prognosis still need to be explored further.
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Kwak-Kim J, AlSubki L, Luu T, Ganieva U, Thees A, Dambaeva S, Gilman-Sachs A. The role of immunologic tests for subfertility in the clinical environment. Fertil Steril 2022; 117:1132-1143. [DOI: 10.1016/j.fertnstert.2022.04.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/17/2022] [Accepted: 04/06/2022] [Indexed: 11/04/2022]
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An HDAC9-associated immune-related signature predicts bladder cancer prognosis. PLoS One 2022; 17:e0264527. [PMID: 35239708 PMCID: PMC8893690 DOI: 10.1371/journal.pone.0264527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 02/12/2022] [Indexed: 02/07/2023] Open
Abstract
Background The close relationship between histone deacetylase 9 (HDAC9) and immunity has attracted attention. We constructed an immune signature for HDAC9, a vital epigenetic modification, to predict the survival status and treatment benefits in bladder cancer (BC). Methods An exhaustive analysis of HDAC9 and immunology via the tumor and immune system interaction database (TISIDB) was performed, and an immune prognostic risk signature was developed based on genes enriched in the top five immune-related pathways under high HDAC9 status. Comprehensive analysis of survival curves and Cox regression were used to estimate the effectiveness of the risk signature. The relationship between immunological characteristics and the risk score was evaluated, and the mechanisms were also explored. Results In the TISIDB, HDAC9 was closely related to various immunological characteristics. The risk signature was obtained based on genes related to prognosis enriched in the top five immune-related pathways under high HDAC9 status. The survival rate of the high-risk BC patients was poor. The risk score was closely related to multiple immunological characteristics, drug sensitivity, immunotherapy benefits and biofunctions. Conclusion An immune-related prognostic signature established for HDAC9 expression status could independently predict the prognosis of BC patients. The use of this signature could help clinicians make personalized treatment decisions.
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Turner DJ, Saveliev A, Salerno F, Matheson LS, Screen M, Lawson H, Wotherspoon D, Kranc KR, Turner M. A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells. eLife 2022; 11:e72313. [PMID: 35451955 PMCID: PMC9106329 DOI: 10.7554/elife.72313] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 04/21/2022] [Indexed: 12/02/2022] Open
Abstract
To identify roles of RNA binding proteins (RBPs) in the differentiation or survival of antibody secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the abundance of differentiated CD138 + cells in vitro. We validated the binding partners CSDE1 and STRAP as well as the m6A binding protein YTHDF2 as promoting the accumulation of CD138 + cells in vitro. We validated the EIF3 subunits EIF3K and EIF3L and components of the CCR4-NOT complex as inhibitors of CD138 + cell accumulation in vitro. In chimeric mouse models YTHDF2-deficient plasma cells failed to accumulate.
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Affiliation(s)
- David J Turner
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
- RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute (NCI)FrederickUnited States
| | - Alexander Saveliev
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
| | - Fiamma Salerno
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
| | - Louise S Matheson
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
| | - Michael Screen
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
| | - Hannah Lawson
- Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Queen Mary University of LondonLondonUnited Kingdom
| | - David Wotherspoon
- Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Queen Mary University of LondonLondonUnited Kingdom
| | - Kamil R Kranc
- Laboratory of Haematopoietic Stem Cell and Leukaemia Biology, Queen Mary University of LondonLondonUnited Kingdom
| | - Martin Turner
- Immunology Programme, The Babraham Institute,Babraham Research CampusCambridgeUnited Kingdom
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Caballero-Solares A, Umasuthan N, Xue X, Katan T, Kumar S, Westcott JD, Chen Z, Fast MD, Skugor S, Taylor RG, Rise ML. Interacting Effects of Sea Louse (Lepeophtheirus salmonis) Infection and Formalin-Killed Aeromonas salmonicida on Atlantic Salmon Skin Transcriptome. Front Immunol 2022; 13:804987. [PMID: 35401509 PMCID: PMC8987027 DOI: 10.3389/fimmu.2022.804987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Lepeophtheirus salmonis (sea lice) and bacterial co-infection threatens wild and farmed Atlantic salmon performance and welfare. In the present study, pre-adult L. salmonis-infected and non-infected salmon were intraperitoneally injected with either formalin-killed Aeromonas salmonicida bacterin (ASAL) or phosphate-buffered saline (PBS). Dorsal skin samples from each injection/infection group (PBS/no lice, PBS/lice, ASAL/no lice, and ASAL/lice) were collected at 24 h post-injection and used for transcriptome profiling using a 44K salmonid microarray platform. Microarray results showed no clear inflammation gene expression signatures and revealed extensive gene repression effects by pre-adult lice (2,189 down and 345 up-regulated probes) in the PBS-injected salmon (PBS/lice vs. PBS/no lice), which involved basic cellular (e.g., RNA and protein metabolism) processes. Lice repressive effects were not observed within the group of ASAL-injected salmon (ASAL/lice vs. ASAL/no lice); on the contrary, the observed skin transcriptome changes –albeit of lesser magnitude (82 up and 1 down-regulated probes)– suggested the activation in key immune and wound healing processes (e.g., neutrophil degranulation, keratinocyte differentiation). The molecular skin response to ASAL was more intense in the lice-infected (ASAL/lice vs. PBS/lice; 272 up and 11 down-regulated probes) than in the non-infected fish (ASAL/no lice vs. PBS/no lice; 27 up-regulated probes). Regardless of lice infection, the skin’s response to ASAL was characterized by the putative activation of both antibacterial and wound healing pathways. The transcriptomic changes prompted by ASAL+lice co-stimulation (ASAL/lice vs. PBS/no lice; 1878 up and 3120 down-regulated probes) confirmed partial mitigation of lice repressive effects on fundamental cellular processes and the activation of pathways involved in innate (e.g., neutrophil degranulation) and adaptive immunity (e.g., antibody formation), as well as endothelial cell migration. The qPCR analyses evidenced immune-relevant genes co-stimulated by ASAL and lice in an additive (e.g., mbl2b, bcl6) and synergistic (e.g., hampa, il4r) manner. These results provided insight on the physiological response of the skin of L. salmonis-infected salmon 24 h after ASAL stimulation, which revealed immunostimulatory properties by the bacterin with potential applications in anti-lice treatments for aquaculture. As a simulated co-infection model, the present study also serves as a source of candidate gene biomarkers for sea lice and bacterial co-infection.
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Affiliation(s)
- Albert Caballero-Solares
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
- *Correspondence: Albert Caballero-Solares,
| | | | - Xi Xue
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
| | - Tomer Katan
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
| | - Surendra Kumar
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
| | | | - Zhiyu Chen
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
- Fisheries and Marine Institute, Memorial University, St. John’s, NL, Canada
| | - Mark D. Fast
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada
| | - Stanko Skugor
- Cargill Aqua Nutrition, Cargill, Sea Lice Research Center (SLRC), Sandnes, Norway
| | | | - Matthew L. Rise
- Department of Ocean Sciences, Memorial University, St. John’s, NL, Canada
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Hoshino Y, Noto D, Sano S, Tomizawa Y, Yokoyama K, Hattori N, Miyake S. Dysregulated B cell differentiation towards antibody-secreting cells in neuromyelitis optica spectrum disorder. J Neuroinflammation 2022; 19:6. [PMID: 34991631 PMCID: PMC8740356 DOI: 10.1186/s12974-021-02375-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/28/2021] [Indexed: 11/24/2022] Open
Abstract
Background Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism involved in AQP4-Ab production remains unclear. Methods We analyzed the immunophenotypes of patients with NMOSD and other neuroinflammatory diseases as well as healthy controls (HC) using flow cytometry. Transcriptome analysis of B cell subsets obtained from NMOSD patients and HCs was performed. The differentiation capacity of B cell subsets into antibody-secreting cells was analyzed. Results The frequencies of switched memory B (SMB) cells and plasmablasts were increased and that of naïve B cells was decreased in NMOSD patients compared with relapsing–remitting multiple sclerosis patients and HC. SMB cells from NMOSD patients had an enhanced potential to differentiate into antibody-secreting cells when cocultured with T peripheral helper cells. Transcriptome analysis revealed that the profiles of B cell lineage transcription factors in NMOSD were skewed towards antibody-secreting cells and that IL-2 signaling was upregulated, particularly in naïve B cells. Naïve B cells expressing CD25, a receptor of IL-2, were increased in NMOSD patients and had a higher potential to differentiate into antibody-secreting cells, suggesting CD25+ naïve B cells are committed to differentiate into antibody-secreting cells. Conclusions To the best of our knowledge, this is the first study to demonstrate that B cells in NMOSD patients are abnormally skewed towards antibody-secreting cells at the transcriptome level during the early differentiation phase, and that IL-2 might participate in this pathogenic process. Our study indicates that CD25+ naïve B cells are a novel candidate precursor of antibody-secreting cells in autoimmune diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02375-w.
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Affiliation(s)
- Yasunobu Hoshino
- Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Daisuke Noto
- Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Shuhei Sano
- Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yuji Tomizawa
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazumasa Yokoyama
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sachiko Miyake
- Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
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Chen X, Song QL, Ji R, Wang JY, Li ZH, Guo D, Yin TL, Wang SJ, Yang J. MiR-187 regulates the proliferation, migration and invasion of human trophoblast cells by repressing BCL6-mediated activation of PI3K/AKT signaling. Placenta 2022; 118:20-31. [PMID: 35007926 DOI: 10.1016/j.placenta.2022.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/30/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Recurrent miscarriage (RM), refers to two or more consecutive spontaneous miscarriage in a pregnant woman. RM is caused by many factors, and microRNAs play an important role in the development and pathology of RM. In the present study, we investigated the function of miR-187 in the pathogenesis of RM and its effects on human trophoblast cells. METHODS The localization of miR-187 in the human placenta in early pregnancy was determined by in situ hybridization. QRT-PCR was used to detect the expression of miR-187 in villi of normal early pregnancy induced abortion group and recurrent spontaneous miscarriage group. Then, HTR8/SVneo cells were used to investigated the effect of miR-187 on BCL6 expression and biological activity of trophoblasts. RESULTS We found that the expression of miR-187 in villi of RM group was higher than that of normal abortion group and miR-187 inhibited the proliferation, migration, and invasion of HTR8 cells. We also found that miR-187 promoted apoptosis, inhibited EMT, and inhibited the PI3K/AKT pathway in HTR8 cells. In addition, we also found that BCL6 is a direct target of miR-187 and is negatively regulated by miR-187. In addition, BCL6 reversed the inhibitory effects of miR-187 on HTR8/SVneo cells. These data demonstrate that miR-187-induced repression of PI3K/AKT signaling is mediated by BCL6 in HTR8 cells. DISSCUSSION MiR-187 inhibits the proliferation, migration, and invasion of trophoblasts through a mechanism that involves regulation of BCL6.
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Affiliation(s)
- Xin Chen
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China
| | - Qian Lin Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, PR China
| | - Rui Ji
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China
| | - Jia Yu Wang
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China
| | - Ze Hong Li
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China
| | - DuanYing Guo
- Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, PR China
| | - Tai Lang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China.
| | - Shao Juan Wang
- Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, PR China.
| | - Jing Yang
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, 430060, PR China.
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Horiguchi H, Xu H, Duvert B, Ciuculescu F, Yao Q, Sinha A, McGuinness M, Harris C, Brendel C, Troeger A, Chiarle R, Williams DA. Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma. Small GTPases 2022; 13:267-281. [PMID: 34983288 PMCID: PMC8741284 DOI: 10.1080/21541248.2021.2019503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
RHOH/TFF, a member of the RAS GTPase super family, has important functions in lymphopoiesis and proximal T cell receptor signalling and has been implicated in a variety of leukaemias and lymphomas. RHOH was initially identified as a translocation partner with BCL-6 in non-Hodgkin lymphoma (NHL), and aberrant somatic hypermutation (SHM) in the 5' untranslated region of the RHOH gene has also been detected in Diffuse Large B-Cell Lymphoma (DLBCL). Recent data suggest a correlation between RhoH expression and disease progression in Acute Myeloid Leukaemia (AML). However, the effects of RHOH mutations and translocations on RhoH expression and malignant transformation remain unknown. We found that aged Rhoh-/- (KO) mice had shortened lifespans and developed B cell derived splenomegaly with an increased Bcl-6 expression profile in splenocytes. We utilized a murine model of Bcl-6 driven DLBCL to further explore the role of RhoH in malignant behaviour by crossing RhohKO mice with Iµ-HABcl-6 transgenic (Bcl-6Tg) mice. The loss of Rhoh in Bcl-6Tg mice led to a more rapid disease progression. Mechanistically, we demonstrated that deletion of Rhoh in these murine lymphoma cells was associated with decreased levels of the RhoH binding partner KAISO, a dual-specific Zinc finger transcription factor, de-repression of KAISO target Bcl-6, and downregulation of the BCL-6 target Blimp-1. Re-expression of RhoH in RhohKOBcl-6Tg lymphoma cell lines reversed these changes in expression profile and reduced proliferation of lymphoma cells in vitro. These findings suggest a previously unidentified regulatory role of RhoH in the proliferation of tumour cells via altered BCL-6 expression. (250).
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Affiliation(s)
- Hiroto Horiguchi
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Haiming Xu
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Beatrice Duvert
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Felicia Ciuculescu
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Qiuming Yao
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Meaghan McGuinness
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Chad Harris
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Christian Brendel
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Harvard Stem Cell Institute, Harvard University, Boston, MA, USA
| | - Anja Troeger
- Division of Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, University Hospital Regensburg, Regensburg, Bavaria, Germany
| | - Roberto Chiarle
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - David A. Williams
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Harvard Stem Cell Institute, Harvard University, Boston, MA, USA,Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA, USA,CONTACT David A. Williams Division of Hematology/Oncology, Boston Children’s Hospital, 300 Longwood Ave. Karp 08125.3, Boston, MA02115, USA
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Rauschmeier R, Reinhardt A, Gustafsson C, Glaros V, Artemov AV, Dunst J, Taneja R, Adameyko I, Månsson R, Busslinger M, Kreslavsky T. Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis. J Exp Med 2021; 219:212923. [PMID: 34919144 PMCID: PMC8689665 DOI: 10.1084/jem.20211406] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/01/2021] [Accepted: 11/23/2021] [Indexed: 12/22/2022] Open
Abstract
The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
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Affiliation(s)
- René Rauschmeier
- Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
| | - Annika Reinhardt
- Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Charlotte Gustafsson
- Center for Hematology and Regenerative Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Vassilis Glaros
- Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Artem V. Artemov
- Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria
- Endocrinology Research Centre, Moscow, Russian Federation
| | - Josefine Dunst
- Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Reshma Taneja
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Igor Adameyko
- Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Robert Månsson
- Center for Hematology and Regenerative Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Hematology Center, Karolinska University Hospital, Stockholm, Sweden
| | - Meinrad Busslinger
- Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
| | - Taras Kreslavsky
- Department of Medicine, Division of Immunology and Allergy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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44
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Soshnev AA, Allis CD, Cesarman E, Melnick AM. Histone H1 Mutations in Lymphoma: A Link(er) between Chromatin Organization, Developmental Reprogramming, and Cancer. Cancer Res 2021; 81:6061-6070. [PMID: 34580064 PMCID: PMC8678342 DOI: 10.1158/0008-5472.can-21-2619] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/10/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022]
Abstract
Aberrant cell fate decisions due to transcriptional misregulation are central to malignant transformation. Histones are the major constituents of chromatin, and mutations in histone-encoding genes are increasingly recognized as drivers of oncogenic transformation. Mutations in linker histone H1 genes were recently identified as drivers of peripheral lymphoid malignancy. Loss of H1 in germinal center B cells results in widespread chromatin decompaction, redistribution of core histone modifications, and reactivation of stem cell-specific transcriptional programs. This review explores how linker histones and mutations therein regulate chromatin structure, highlighting reciprocal relationships between epigenetic circuits, and discusses the emerging role of aberrant three-dimensional chromatin architecture in malignancy.
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Affiliation(s)
- Alexey A Soshnev
- Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York.
| | - C David Allis
- Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York
| | - Ethel Cesarman
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Ari M Melnick
- Division of Hematology & Medical Oncology, Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York.
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45
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Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, Vermeulen J, Shreeve M, Staudt LM. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell 2021; 39:1643-1653.e3. [PMID: 34739844 PMCID: PMC8722194 DOI: 10.1016/j.ccell.2021.10.006] [Citation(s) in RCA: 198] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/31/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.
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Affiliation(s)
- Wyndham H Wilson
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - George W Wright
- Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, USA
| | - Da Wei Huang
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Brendan Hodkinson
- Johnson & Johnson, 1 Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA
| | | | - Yue Fan
- Johnson & Johnson, 1 Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA
| | - Jessica Vermeulen
- Johnson & Johnson, 1 Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA
| | - Martin Shreeve
- Johnson & Johnson, 1 Johnson & Johnson Plaza, New Brunswick, NJ 08933, USA
| | - Louis M Staudt
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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46
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Gaudette BT, Roman CJ, Ochoa TA, Gómez Atria D, Jones DD, Siebel CW, Maillard I, Allman D. Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation. J Clin Invest 2021; 131:e151975. [PMID: 34473651 DOI: 10.1172/jci151975] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022] Open
Abstract
Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1- and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell-affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.
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Affiliation(s)
| | - Carly J Roman
- The Department of Pathology and Laboratory Medicine and
| | - Trini A Ochoa
- The Department of Pathology and Laboratory Medicine and
| | - Daniela Gómez Atria
- The Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Derek D Jones
- The Department of Pathology and Laboratory Medicine and
| | - Christian W Siebel
- Department of Discovery Oncology, Genentech Inc., South San Francisco, California, USA
| | - Ivan Maillard
- The Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David Allman
- The Department of Pathology and Laboratory Medicine and
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Patterson DG, Kania AK, Zuo Z, Scharer CD, Boss JM. Epigenetic gene regulation in plasma cells. Immunol Rev 2021; 303:8-22. [PMID: 34010461 PMCID: PMC8387415 DOI: 10.1111/imr.12975] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Humoral immunity provides protection from pathogenic infection and is mediated by antibodies following the differentiation of naive B cells (nBs) to antibody-secreting cells (ASCs). This process requires substantial epigenetic and transcriptional rewiring to ultimately repress the nB program and replace it with one conducive to ASC physiology and function. Notably, these reprogramming events occur within the framework of cell division. Efforts to understand the relationship of cell division with reprogramming and ASC differentiation in vivo have uncovered the timing and scope of reprogramming, as well as key factors that influence these events. Herein, we discuss the unique physiology of ASC and how nBs undergo epigenetic and genome architectural reorganization to acquire the necessary functions to support antibody production. We also discuss the stage-wise manner in which reprogramming occurs across cell divisions and how key molecular determinants can influence B cell fate outcomes.
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Affiliation(s)
- Dillon G. Patterson
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
| | - Anna K. Kania
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
| | - Zhihong Zuo
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
- Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | | | - Jeremy M. Boss
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
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48
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Yang M, Yi P, Jiang J, Zhao M, Wu H, Lu Q. Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases. Int Rev Immunol 2021; 42:1-25. [PMID: 34445929 DOI: 10.1080/08830185.2021.1964498] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
B cells play a crucial role in antigen presentation, antibody production and pro-/anti-inflammatory cytokine secretion in adaptive immunity. Several translational factors including transcription factors and cytokines participate in the regulation of B cell development, with the cooperation of epigenetic regulations. Autoimmune diseases are generally characterized with autoreactive B cells and high-level pathogenic autoantibodies. The success of B cell depletion therapy in mouse model and clinical trials has proven the role of B cells in pathogenesis of autoimmune diseases. The failure of B cell tolerance in immune checkpoints results in accumulated autoreactive naïve B (BN) cells with aberrant B cell receptor signaling and dysregulated B cell response, contributing to self-antibody-mediated autoimmune reaction. Dysregulation of translational factors and epigenetic alterations in B cells has been demonstrated to correlate with aberrant B cell compartment in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's syndrome, multiple sclerosis, diabetes mellitus and pemphigus. This review is intended to summarize the interaction of translational factors and epigenetic regulations that are involved with development and differentiation of B cells, and the mechanism of dysregulation in the pathogenesis of autoimmune diseases.
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Affiliation(s)
- Ming Yang
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Ping Yi
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Jiao Jiang
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Ming Zhao
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Haijing Wu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.,Department of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China
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49
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Pearce AC, Bamford MJ, Barber R, Bridges A, Convery MA, Demetriou C, Evans S, Gobbetti T, Hirst DJ, Holmes DS, Hutchinson JP, Jayne S, Lezina L, McCabe MT, Messenger C, Morley J, Musso MC, Scott-Stevens P, Manso AS, Schofield J, Slocombe T, Somers D, Walker AL, Wyce A, Zhang XP, Wagner SD. GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice. J Biol Chem 2021; 297:100928. [PMID: 34274316 PMCID: PMC8350397 DOI: 10.1016/j.jbc.2021.100928] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022] Open
Abstract
B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 μg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.
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Affiliation(s)
| | - Mark J Bamford
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | - Ruth Barber
- Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK
| | - Angela Bridges
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | | | - Constantinos Demetriou
- Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK
| | - Sian Evans
- Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK
| | | | - David J Hirst
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | | | | | - Sandrine Jayne
- Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK
| | - Larissa Lezina
- Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK; Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK
| | | | | | - Joanne Morley
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | | | | | - Ana Sousa Manso
- Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK; Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK
| | - Jennifer Schofield
- Leicester Drug Discovery and Diagnostics, University of Leicester, Leicester, UK
| | - Tom Slocombe
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | - Don Somers
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | - Ann L Walker
- GlaxoSmithKline, Medicines Research Centre, Stevenage, UK
| | | | | | - Simon D Wagner
- Leicester Cancer Research Centre and Ernest and Helen Scott Haematological Research Unit, University of Leicester, Leicester, UK.
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50
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Abstract
Worldwide about one million patients are given anti-CD20 antibodies such as rituximab (RTX) for the treatment of B cell-associated diseases. Despite the success of this first therapeutic antibody, little is known about the function of its target. The role of CD20 only becomes clear in the context of the nanoscale compartmentalization of the B lymphocyte membrane. We found that CD20 is an organizer of the IgD-class nanocluster on the B cell membrane. The loss of CD20 on human B cells results in a dissolution of the IgD-class nanocluster and a transient B cell activation inducing a B cell-to-PC differentiation. Thus, CD20 is an essential gatekeeper of a membrane nanodomain and the resting state of naive B cells. CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.
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