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Parekh S. At the cusp of a cure in Myeloma: Insights into pathogenesis, modeling and therapeutics. Semin Hematol 2025; 62:1-2. [PMID: 40090758 DOI: 10.1053/j.seminhematol.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2025]
Affiliation(s)
- Samir Parekh
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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2
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Bergsagel PL, Chesi M. Immunocompetent mouse models of multiple myeloma. Semin Hematol 2025; 62:50-57. [PMID: 39674742 PMCID: PMC11911088 DOI: 10.1053/j.seminhematol.2024.11.003] [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: 09/16/2024] [Revised: 10/30/2024] [Accepted: 11/12/2024] [Indexed: 12/16/2024]
Abstract
Immunocompetent murine models of multiple myeloma are critical for understanding the pathogenesis of multiple myeloma and for the development of novel immunotherapeutics. Different models are available in Balb/c and C57Bl strains, each with different advantages and disadvantages. The availability of many transplantable cell lines allows for the conduct of experiments with large cohorts of mice bearing identical tumors, while cell lines that grow in vitro can be used for genetic manipulations. The introduction of human CRBN into these models allows for the study of IMiDs and cereblon based PROTACs in mice. New genetically engineered models based on germinal center cell activation of Nsd2 or Ccnd1 together with constitutive NFkB are being developed to model some of the important genetic subtypes of human multiple myeloma.
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Affiliation(s)
- Peter Leif Bergsagel
- Department of Medicine, Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85259.
| | - Marta Chesi
- Department of Medicine, Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85259
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3
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Wang Y, Kroll TG, Hao L, Wen Z. Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53. Cell Death Dis 2025; 16:15. [PMID: 39809731 PMCID: PMC11733144 DOI: 10.1038/s41419-025-07337-1] [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: 03/21/2024] [Revised: 11/29/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025]
Abstract
The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.
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Affiliation(s)
- Yidan Wang
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Todd G Kroll
- Department of Pathology, Marshfield Medical Center, Marshfield Clinic Health System, Marshfield, WI, USA
- Department of Pathology and Laboratory Medicine, Endeavor Northshore Health System, Evanston, IL, USA
| | - Linhui Hao
- Institute of Molecular Virology, University of Wisconsin-Madison, Madison, WI, USA
| | - Zhi Wen
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield Clinic Health System, Marshfield, WI, USA.
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4
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Du MT, Bergsagel PL, Chesi M. Immunocompetent Mouse Models of Multiple Myeloma: Therapeutic Implications. Hematol Oncol Clin North Am 2024; 38:533-546. [PMID: 38233233 PMCID: PMC10942746 DOI: 10.1016/j.hoc.2023.12.014] [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: 01/19/2024]
Abstract
Immunocompetent mouse models of multiple myeloma (MM) are particularly needed in the era of T cell redirected therapy to understand drivers of sensitivity and resistance, optimize responses, and prevent toxicities. Three mouse models have been extensively characterized: the Balb/c plasmacytomas, the 5TMM, and the Vk*MYC. In the last year, additional models have been generated, which, for the first time, capture primary MM initiating events, like MMSET/NSD2 or cyclin D1 dysregulation. However, the long latency needed for tumor development and the lack of transplantable lines limit their utilization. Future studies should focus on modeling hyperdiploid MM.
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Affiliation(s)
- Megan Tien Du
- Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, MCCRB 3-040, Scottsdale, AZ 85259, USA
| | - Peter Leif Bergsagel
- Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, MCCRB 3-040, Scottsdale, AZ 85259, USA
| | - Marta Chesi
- Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, MCCRB 3-040, Scottsdale, AZ 85259, USA.
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5
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Li M, Bennett MK, Toubia J, Pope VS, Tea MN, Tamang S, Samuel MS, Anderson PH, Gliddon BL, Powell JA, Pitson SM. An orthotopic syngeneic mouse model of bortezomib-resistant multiple myeloma. Br J Haematol 2024; 204:566-570. [PMID: 38053270 DOI: 10.1111/bjh.19240] [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: 08/17/2023] [Revised: 11/11/2023] [Accepted: 11/21/2023] [Indexed: 12/07/2023]
Abstract
While bortezomib has significant benefits in multiple myeloma (MM) therapy, the disease remains incurable due to the invariable development of bortezomib resistance. This emphasises the need for advanced models for preclinical evaluation of new therapeutic approaches for bortezomib-resistant MM. Here, we describe the development of an orthotopic syngeneic bortezomib-resistant MM mouse model based on the most well-characterised syngeneic MM mouse model derived from spontaneous MM-forming C57BL/KaLwRij mice. Using bortezomib-resistant 5TGM1 cells, we report and characterise a robust syngeneic mouse model of bortezomib-resistant MM that is well suited to the evaluation of new therapeutic approaches for proteasome inhibitor-resistant MM.
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Affiliation(s)
- Manjun Li
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Melissa K Bennett
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - John Toubia
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Victoria S Pope
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Melinda N Tea
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Sarah Tamang
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Michael S Samuel
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Paul H Anderson
- Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Briony L Gliddon
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Jason A Powell
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
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6
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Zhou R, Guo J, Feng X, Zhou W. Mechanisms of the role of proto-oncogene activation in promoting malignant transformation of mature B cells. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:113-121. [PMID: 38615172 PMCID: PMC11017026 DOI: 10.11817/j.issn.1672-7347.2024.230304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Indexed: 04/15/2024]
Abstract
Malignant tumors continue to pose a significant threat to human life and safety and their development is primarily due to the activation of proto-oncogenes and the inactivation of suppressor genes. Among these, the activation of proto-oncogenes possesses greater potential to drive the malignant transformation of cells. Targeting oncogenes involved in the malignant transformation of tumor cells has provided a novel approach for the development of current antitumor drugs. Several preclinical and clinical studies have revealed that the development pathway of B cells, and the malignant transformation of mature B cells into tumors have been regulated by oncogenes and their metabolites. Therefore, summarizing the key oncogenes involved in the process of malignant transformation of mature B cells and elucidating the mechanisms of action in tumor development hold significant importance for the clinical treatment of malignant tumors.
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Affiliation(s)
- Ruiqi Zhou
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha 410078.
| | - Jiaojiao Guo
- Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008
| | - Xiangling Feng
- Xiangya School of Public Health, Central South University, Changsha 410006, China
| | - Wen Zhou
- Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha 410078.
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7
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Perroud C, Thurian D, Andres M, Künzi A, Wiedemann G, Zeerleder S, Bacher U, Pabst T, Banz Y, Porret N, Rebmann E. Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma. Hematol Oncol 2023; 41:912-921. [PMID: 37452600 DOI: 10.1002/hon.3208] [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: 03/19/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone.
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Affiliation(s)
- Camille Perroud
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
- Department of Internal Medicine, Hôpital Cantonal Fribourgeois HFR, Fribourg, Switzerland
| | - Dario Thurian
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
- Department of Internal Medicine, Spital Thun STS AG, Thun, Switzerland
| | - Martin Andres
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Arnaud Künzi
- Clinical Trials Unit, University of Bern, Bern, Switzerland
| | - Gertrud Wiedemann
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Sacha Zeerleder
- Department of Hematology, Kantonsspital Luzern and University of Bern, Luzern, Switzerland
| | - Ulrike Bacher
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Thomas Pabst
- Department of Clinical Oncology, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Yara Banz
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Naomi Porret
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
| | - Ekaterina Rebmann
- Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital of Bern, Bern, Switzerland
- Department of Oncology-Hematology, Hospital of Neuchâtel (RHNe), Neuchâtel, Switzerland
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8
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Lyu T, Yin Q. Research Progress on Pyroptosis in Hematological Malignancies. Curr Treat Options Oncol 2023; 24:1439-1450. [PMID: 37635159 PMCID: PMC10547621 DOI: 10.1007/s11864-023-01119-7] [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] [Accepted: 05/28/2023] [Indexed: 08/29/2023]
Abstract
OPINION STATEMENT Pyroptosis is a kind of programmed cell death dependent on the caspase pathway that is different from apoptosis and necrosis. Recent studies have shown that pyroptosis can be involved in the pathological processes of many diseases, such as cancers, atherosclerosis, diabetic nephropathy, and blood diseases. However, the specific mechanisms by which pyroptosis participates in the occurrence and development of hematological malignant tumors still need further exploration. This article reviews the characteristics of pyroptosis and the regulatory mechanisms promoting or inhibiting pyroptosis and discusses the role of pyroptosis in hematological malignant tumors, which could provide ideas for the clinical treatment of such tumors in the future.
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Affiliation(s)
- Tianxin Lyu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Qingsong Yin
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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9
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Peat TJ, Gaikwad SM, Dubois W, Gyabaah-Kessie N, Zhang S, Gorjifard S, Phyo Z, Andres M, Hughitt VK, Simpson RM, Miller MA, Girvin AT, Taylor A, Williams D, D'Antonio N, Zhang Y, Rajagopalan A, Flietner E, Wilson K, Zhang X, Shinn P, Klumpp-Thomas C, McKnight C, Itkin Z, Chen L, Kazandijian D, Zhang J, Michalowski AM, Simmons JK, Keats J, Thomas CJ, Mock BA. Drug combinations identified by high-throughput screening promote cell cycle transition and upregulate Smad pathways in myeloma. Cancer Lett 2023; 568:216284. [PMID: 37356470 PMCID: PMC10408729 DOI: 10.1016/j.canlet.2023.216284] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 06/27/2023]
Abstract
Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFβ/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity.
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Affiliation(s)
- Tyler J Peat
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
| | - Snehal M Gaikwad
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Wendy Dubois
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Nana Gyabaah-Kessie
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Shuling Zhang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Sayeh Gorjifard
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; University of Washington, Seattle, WA, USA
| | - Zaw Phyo
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Johns Hopkins University, Baltimore, MD, USA
| | - Megan Andres
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Johns Hopkins University, Baltimore, MD, USA
| | - V Keith Hughitt
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - R Mark Simpson
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Margaret A Miller
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
| | | | | | | | | | - Yong Zhang
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | | | - Evan Flietner
- McArdle Research Labs, University of Wisconsin, Madison, WI, USA
| | - Kelli Wilson
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Xiaohu Zhang
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Paul Shinn
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Carleen Klumpp-Thomas
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Crystal McKnight
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Zina Itkin
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Lu Chen
- Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Dickran Kazandijian
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Jing Zhang
- McArdle Research Labs, University of Wisconsin, Madison, WI, USA
| | - Aleksandra M Michalowski
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Jonathan Keats
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Craig J Thomas
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Chemical Genomics Center, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Bethesda, MD, USA
| | - Beverly A Mock
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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10
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Flietner E, Yu M, Poudel G, Veltri AJ, Zhou Y, Rajagopalan A, Feng Y, Lasho T, Wen Z, Sun Y, Patnaik MM, Callander NS, Asimakopoulos F, Wang D, Zhang J. Molecular characterization stratifies VQ myeloma cells into two clusters with distinct risk signatures and drug responses. Oncogene 2023; 42:1751-1762. [PMID: 37031341 PMCID: PMC10367583 DOI: 10.1038/s41388-023-02684-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 04/10/2023]
Abstract
Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. The various VQ lines display different disease phenotypes and survival rates, suggesting significant intra-model variation. Here, we use whole-exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify the VQ lines into corresponding clusters: Group A cells had monosomy chromosome (chr) 5 and overexpressed genes and pathways associated with sensitivity to bortezomib (Btz) treatment in human MM patients. By contrast, Group B VQ cells carried recurrent amplification (Amp) of chr3 and displayed high-risk MM features, including downregulation of Fam46c, upregulation of cancer growth pathways associated with functional high-risk MM, and expression of Amp1q and high-risk UAMS-70 and EMC-92 gene signatures. Consistently, in sharp contrast to Group A VQ cells that showed short-term response to Btz, Group B VQ cells were de novo resistant to Btz in vivo. Our study highlights Group B VQ lines as highly representative of the human MM subset with ultrahigh risk.
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Affiliation(s)
- Evan Flietner
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Mei Yu
- Versiti Blood Research Institute, Milwaukee, WI, 53226, USA
| | - Govinda Poudel
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | | | - Yun Zhou
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Adhithi Rajagopalan
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Yubin Feng
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Terra Lasho
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55902, USA
| | - Zhi Wen
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA
| | - Yuqian Sun
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55902, USA
| | - Natalie S Callander
- Division of Hematology/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Demin Wang
- Versiti Blood Research Institute, Milwaukee, WI, 53226, USA.
| | - Jing Zhang
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA.
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11
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Winkler W, Farré Díaz C, Blanc E, Napieczynska H, Langner P, Werner M, Walter B, Wollert-Wulf B, Yasuda T, Heuser A, Beule D, Mathas S, Anagnostopoulos I, Rosenwald A, Rajewsky K, Janz M. Mouse models of human multiple myeloma subgroups. Proc Natl Acad Sci U S A 2023; 120:e2219439120. [PMID: 36853944 PMCID: PMC10013859 DOI: 10.1073/pnas.2219439120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/26/2023] [Indexed: 03/01/2023] Open
Abstract
Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated genetically defined, subgroup-specific MM models by the GC B cell-specific coactivation of mouse Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NF-κB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency, and bone lesions. The transgenic plasma cells could be propagated in vivo and showed distinct transcriptional profiles, resembling their human MM counterparts. Thus, we show that targeting the expression of genes involved in MM subgroup-specific chromosomal translocations into mouse GC B cells translates into distinct MM-like diseases that recapitulate key features of the human tumors, opening the way to a better understanding of the pathogenesis and therapeutic vulnerabilities of different MM subgroups.
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Affiliation(s)
- Wiebke Winkler
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Carlota Farré Díaz
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Eric Blanc
- Core Unit Bioinformatics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin10117, Germany
| | - Hanna Napieczynska
- Animal Phenotyping, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
| | - Patrick Langner
- Animal Phenotyping, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
| | - Marvin Werner
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Barbara Walter
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Brigitte Wollert-Wulf
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Tomoharu Yasuda
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
| | - Arnd Heuser
- Animal Phenotyping, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
| | - Dieter Beule
- Core Unit Bioinformatics, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin10117, Germany
| | - Stephan Mathas
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
| | - Ioannis Anagnostopoulos
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken, Würzburg97080, Germany
| | - Andreas Rosenwald
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken, Würzburg97080, Germany
| | - Klaus Rajewsky
- Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
| | - Martin Janz
- Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin13125, Germany
- Experimental and Clinical Research Center, a cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin13125, Germany
- Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Berlin13125, Germany
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12
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Larrayoz M, Garcia-Barchino MJ, Celay J, Etxebeste A, Jimenez M, Perez C, Ordoñez R, Cobaleda C, Botta C, Fresquet V, Roa S, Goicoechea I, Maia C, Lasaga M, Chesi M, Bergsagel PL, Larrayoz MJ, Calasanz MJ, Campos-Sanchez E, Martinez-Cano J, Panizo C, Rodriguez-Otero P, Vicent S, Roncador G, Gonzalez P, Takahashi S, Katz SG, Walensky LD, Ruppert SM, Lasater EA, Amann M, Lozano T, Llopiz D, Sarobe P, Lasarte JJ, Planell N, Gomez-Cabrero D, Kudryashova O, Kurilovich A, Revuelta MV, Cerchietti L, Agirre X, San Miguel J, Paiva B, Prosper F, Martinez-Climent JA. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma. Nat Med 2023; 29:632-645. [PMID: 36928817 PMCID: PMC10033443 DOI: 10.1038/s41591-022-02178-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 12/09/2022] [Indexed: 03/17/2023]
Abstract
The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
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Affiliation(s)
- Marta Larrayoz
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Maria J Garcia-Barchino
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Jon Celay
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Amaia Etxebeste
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Maddalen Jimenez
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Cristina Perez
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Raquel Ordoñez
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Cesar Cobaleda
- Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain
| | - Cirino Botta
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Vicente Fresquet
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Sergio Roa
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Ibai Goicoechea
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Catarina Maia
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Miren Lasaga
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Marta Chesi
- Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - P Leif Bergsagel
- Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Maria J Larrayoz
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Maria J Calasanz
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Elena Campos-Sanchez
- Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain
| | - Jorge Martinez-Cano
- Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas/Universidad Autonoma, Madrid, Spain
| | - Carlos Panizo
- Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
| | - Paula Rodriguez-Otero
- Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
| | - Silvestre Vicent
- Program in Solid Tumors, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBERONC, Pamplona, Spain
| | - Giovanna Roncador
- Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain
| | - Patricia Gonzalez
- Monoclonal Antibodies Unit, Biotechnology Program, Spanish National Cancer Research Centre CNIO, Madrid, Spain
| | - Satoru Takahashi
- Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Samuel G Katz
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Loren D Walensky
- Department of Pediatric Oncology and Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Shannon M Ruppert
- Oncology Biomarker Development, Genentech, South San Francisco, CA, USA
| | - Elisabeth A Lasater
- Department of Translational Oncology, Genentech, South San Francisco, CA, USA
| | - Maria Amann
- Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland
| | - Teresa Lozano
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Diana Llopiz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Juan J Lasarte
- Program of Immunology and Immunotherapy, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, CIBEREHD, Pamplona, Spain
| | - Nuria Planell
- Translational Bioinformatics Unit, Navarra-Biomed, Public University of Navarra, IDISNA, Pamplona, Spain
| | - David Gomez-Cabrero
- Translational Bioinformatics Unit, Navarra-Biomed, Public University of Navarra, IDISNA, Pamplona, Spain
- Biological and Environmental Sciences & Engineering Division, King Abdullah University of Science & Technology, Thuwal, Kingdom of Saudi Arabia
| | | | | | - Maria V Revuelta
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Leandro Cerchietti
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Xabier Agirre
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
| | - Jesus San Miguel
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
- Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
| | - Bruno Paiva
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
- Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
| | - Felipe Prosper
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain
- Department of Hematology, Clinica Universidad de Navarra, CCUN, IDISNA, CIBERONC, Pamplona, Spain
| | - Jose A Martinez-Climent
- Division of Hemato-Oncology, Center for Applied Medical Research CIMA, Cancer Center University of Navarra (CCUN), Navarra Institute for Health Research (IDISNA), CIBERONC, Pamplona, Spain.
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13
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Liang Y, He H, Wang W, Wang H, Mo S, Fu R, Liu X, Song Q, Xia Z, Wang L. Malignant clonal evolution drives multiple myeloma cellular ecological diversity and microenvironment reprogramming. Mol Cancer 2022; 21:182. [PMID: 36131282 PMCID: PMC9492468 DOI: 10.1186/s12943-022-01648-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/27/2022] [Indexed: 11/14/2022] Open
Abstract
Background Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression. Methods In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data. Results The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients. Conclusions This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01648-z.
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Affiliation(s)
- Yuanzheng Liang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Haiyan He
- Department of Hematology, Myeloma & Lymphoma Center, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Weida Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Henan Wang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Shaowen Mo
- Clinical Research Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.,Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.,Department of Basic Science, YuanDong International Academy of Life Sciences, Hong Kong, 999077, China.,Experimental Center of BIOQGene, YuanDong International Academy of Life Sciences, Hong Kong, 999077, China
| | - Ruiying Fu
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Xindi Liu
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Qiong Song
- Clinical Research Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China
| | - Zhongjun Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China
| | - Liang Wang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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14
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Papadas A, Deb G, Cicala A, Officer A, Hope C, Pagenkopf A, Flietner E, Morrow ZT, Emmerich P, Wiesner J, Arauz G, Bansal V, Esbona K, Capitini CM, Matkowskyj KA, Deming DA, Politi K, Abrams SI, Harismendy O, Asimakopoulos F. Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment. Cell Rep 2022; 40:111201. [PMID: 35977482 PMCID: PMC9402878 DOI: 10.1016/j.celrep.2022.111201] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 06/10/2022] [Accepted: 07/20/2022] [Indexed: 11/24/2022] Open
Abstract
Stimulatory type 1 conventional dendritic cells (cDC1s) engage in productive interactions with CD8+ effectors along tumor-stroma boundaries. The paradoxical accumulation of “poised” cDC1s within stromal sheets is unlikely to simply reflect passive exclusion from tumor cores. Drawing parallels with embryonic morphogenesis, we hypothesized that invasive margin stromal remodeling generates developmentally conserved cell fate cues that regulate cDC1 behavior. We find that, in human T cell-inflamed tumors, CD8+ T cells penetrate tumor nests, whereas cDC1s are confined within adjacent stroma that recurrently displays site-specific proteolysis of the matrix proteoglycan versican (VCAN), an essential organ-sculpting modification in development. VCAN is necessary, and its proteolytic fragment (matrikine) versikine is sufficient for cDC1 accumulation. Versikine does not influence tumor-seeding pre-DC differentiation; rather, it orchestrates a distinctive cDC1 activation program conferring exquisite sensitivity to DNA sensing, supported by atypical innate lymphoid cells. Thus, peritumoral stroma mimicking embryonic provisional matrix remodeling regulates cDC1 abundance and activity to elicit T cell-inflamed tumor microenvironments. T cell-inflamed tumor microenvironments are a prerequisite for immunotherapy efficacy; however, why some tumors are inflamed and others not remains poorly understood. Papadas et al. link stromal reaction dynamics with T cell-induced inflammation. Peritumoral stroma emulating embryonic provisional matrix remodeling regulates cDC1-NK-CD8+ crosstalk to promote T cell repriming and penetration into tumor nests.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Gauri Deb
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Adam Officer
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Division of Biomedical Informatics, Department of Medicine, University of California, San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Chelsea Hope
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Adam Pagenkopf
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Evan Flietner
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Zachary T Morrow
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Philip Emmerich
- Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Joshua Wiesner
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Garrett Arauz
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Varun Bansal
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA
| | - Karla Esbona
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Christian M Capitini
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Division of Hematology and Oncology, Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, USA
| | - Kristina A Matkowskyj
- UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Dustin A Deming
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Katerina Politi
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Olivier Harismendy
- Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA; Division of Biomedical Informatics, Department of Medicine, University of California, San Diego (UCSD), Moores Cancer Center, La Jolla, CA, USA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego (UCSD), La Jolla, CA, USA.
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15
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Flietner E, Wen Z, Rajagopalan A, Jung O, Watkins L, Wiesner J, You X, Zhou Y, Sun Y, Kingstad-Bakke B, Callander NS, Rapraeger A, Suresh M, Asimakopoulos F, Zhang J. Ponatinib sensitizes myeloma cells to MEK inhibition in the high-risk VQ model. Sci Rep 2022; 12:10616. [PMID: 35739276 PMCID: PMC9226136 DOI: 10.1038/s41598-022-14114-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/01/2022] [Indexed: 11/08/2022] Open
Abstract
Multiple myeloma (MM) is a malignant plasma cell cancer. Mutations in RAS pathway genes are prevalent in advanced and proteasome inhibitor (PI) refractory MM. As such, we recently developed a VQ MM mouse model recapitulating human advanced/high-risk MM. Using VQ MM cell lines we conducted a repurposing screen of 147 FDA-approved anti-cancer drugs with or without trametinib (Tra), a MEK inhibitor. Consistent with its high-risk molecular feature, VQ MM displayed reduced responses to PIs and de novo resistance to the BCL2 inhibitor, venetoclax. Ponatinib (Pon) is the only tyrosine kinase inhibitor that showed moderate MM killing activity as a single agent and strong synergism with Tra in vitro. Combined Tra and Pon treatment significantly prolonged the survival of VQ MM mice regardless of treatment schemes. However, this survival benefit was moderate compared to that of Tra alone. Further testing of Tra and Pon on cytotoxic CD8+ T cells showed that Pon, but not Tra, blocked T cell function in vitro, suggesting that the negative impact of Pon on T cells may partially counteract its MM-killing synergism with Tra in vivo. Our study provides strong rational to comprehensively evaluate agents on both MM cells and anti-MM immune cells during therapy development.
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Affiliation(s)
- Evan Flietner
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Zhi Wen
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA
- Center for Precision Medicine Research and Integrated Research and Development Laboratories, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA
| | - Adhithi Rajagopalan
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - Oisun Jung
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - Lyndsay Watkins
- Center for Precision Medicine Research and Integrated Research and Development Laboratories, Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA
| | - Joshua Wiesner
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Xiaona You
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - Yun Zhou
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - Yuqian Sun
- Department of Biology, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Brock Kingstad-Bakke
- Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Natalie S Callander
- Division of Hematology/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Alan Rapraeger
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705, USA
| | - M Suresh
- Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Fotis Asimakopoulos
- Division of Hematology/Oncology, Department of Medicine, UW Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California-San Diego, La Jolla, CA, 92093, USA
| | - Jing Zhang
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Room 7453, WIMR II, 1111 Highland Avenue, Madison, WI, 53705, USA.
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16
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Liu LT, Wei XJ, Gong LX, Yu Z, Qiu LG, Hao M. [Establishment and comparison of three human multiple myeloma cell line transplantation models in mice]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:414-419. [PMID: 35680600 PMCID: PMC9250955 DOI: 10.3760/cma.j.issn.0253-2727.2022.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Indexed: 11/24/2022]
Abstract
Objective: To establish three types of xenotransplantation models using human myeloma cell lines ARP1, MM.1S, and NCI-H929 and to compare the proliferation, tumor load, and biological characteristics of the three types of cells after transplantation. Methods: Suspensions of human myeloma cell lines ARP1, MM.1S, and NCI-H929 were implanted into NOD/SCID mice by subcutaneous injection or tail vein injection. The survival of the mice was observed weekly, and the tumor load was measured. Flow cytometry was used to detect the proportion of CD138(+) cells in tumor tissue or the mouse bone marrow. CD138(+) cells and light chains were detected by immunofluorescence. Light chains in bone marow and peipheral blood were measured by ELISA, and bone disease was assessed by micro-CT. Results: Mice injected with ARP1, MM.1S, and NCI-H929 cells all formed tumors subcutaneously in about 2 weeks. Immunofluorescence detection supported plasma cell tumors. Kappa light chains were detected in the peripheral blood of ARP1 mice on day 20 after tail vein transplantation (8.2±1.0 ng/ml) . After 6 weeks of tail vein transplantation, mice in the ARP1 group showed signs of weight loss, mental depression, and dragging legs, and human CD138(+)CD38(+) cells were detected in the bone marrow (BM) . Furthermore, bortezomib (BTZ) treatment given once the tumor was established significantly reduced the tumor burden[ (5.7±0.2) % vs (21.3±2.1) %, P<0.01]. Human CD138(+)CD38(+) cells were not detected in the BM of the MM.1S or NCI-H929 groups. Conclusion: The results of this study suggest that the mouse models constructed by the three cell lines (ARP1, MM.1S, and NCI-H929) can be used as models for the pathogenesis and clinical research of MM.
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Affiliation(s)
- L T Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - X J Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - L X Gong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Z Yu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - L G Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - M Hao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
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17
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Vendramini E, Bomben R, Pozzo F, Bittolo T, Tissino E, Gattei V, Zucchetto A. KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:666. [PMID: 35158933 PMCID: PMC8833570 DOI: 10.3390/cancers14030666] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology.
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Affiliation(s)
- Elena Vendramini
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (R.B.); (F.P.); (T.B.); (E.T.); (V.G.); (A.Z.)
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18
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Podar K, Leleu X. Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond. Cancers (Basel) 2021; 13:5154. [PMID: 34680303 PMCID: PMC8534171 DOI: 10.3390/cancers13205154] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/07/2021] [Accepted: 10/10/2021] [Indexed: 12/14/2022] Open
Abstract
Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody-drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on "Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond" summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.
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Affiliation(s)
- Klaus Podar
- Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Xavier Leleu
- Department of Hematology, and CIC1402 INSERM Unit, Poitiers University Hospital, 2 Rue de la Milétrie, 86021 Poitiers, France;
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19
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Pisano M, Cheng Y, Sun F, Dhakal B, D’Souza A, Chhabra S, Knight JM, Rao S, Zhan F, Hari P, Janz S. Laboratory Mice - A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma. Front Immunol 2021; 12:667054. [PMID: 34149703 PMCID: PMC8206561 DOI: 10.3389/fimmu.2021.667054] [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: 02/11/2021] [Accepted: 04/28/2021] [Indexed: 11/13/2022] Open
Abstract
Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.
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Affiliation(s)
- Michael Pisano
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, United States
| | - Yan Cheng
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Fumou Sun
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Binod Dhakal
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Anita D’Souza
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Saurabh Chhabra
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Jennifer M. Knight
- Departments of Psychiatry, Medicine, and Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Sridhar Rao
- Division of Hematology, Oncology and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI, United States
| | - Fenghuang Zhan
- Myeloma Center, Department of Internal Medicine and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Parameswaran Hari
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Siegfried Janz
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
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20
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The winding road toward the myeloma mouse. Blood 2021; 137:7-8. [PMID: 33410904 DOI: 10.1182/blood.2020007942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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21
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Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13030396. [PMID: 33494394 PMCID: PMC7865460 DOI: 10.3390/cancers13030396] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/17/2022] Open
Abstract
Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.
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22
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Papadas A, Arauz G, Cicala A, Wiesner J, Asimakopoulos F. Versican and Versican-matrikines in Cancer Progression, Inflammation, and Immunity. J Histochem Cytochem 2020; 68:871-885. [PMID: 32623942 PMCID: PMC7711242 DOI: 10.1369/0022155420937098] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/04/2020] [Indexed: 12/16/2022] Open
Abstract
Versican is an extracellular matrix proteoglycan with key roles in multiple facets of cancer development, ranging from proliferative signaling, evasion of growth-suppressor pathways, regulation of cell death, promotion of neoangiogenesis, and tissue invasion and metastasis. Multiple lines of evidence implicate versican and its bioactive proteolytic fragments (matrikines) in the regulation of cancer inflammation and antitumor immune responses. The understanding of the dynamics of versican deposition/accumulation and its proteolytic turnover holds potential for the development of novel immune biomarkers as well as approaches to reset the immune thermostat of tumors, thus promoting efficacy of modern immunotherapies. This article summarizes work from several laboratories, including ours, on the role of this central matrix proteoglycan in tumor progression as well as tumor-immune cell cross-talk.
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Affiliation(s)
- Athanasios Papadas
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
- Cellular & Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, WI
| | - Garrett Arauz
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Alexander Cicala
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Joshua Wiesner
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Fotis Asimakopoulos
- Division of Blood and Marrow Transplantation, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA
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