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1
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Chen CH, Chen TC, Wu TS, Hsiao TH, Chen JMM, Huang CYF, Cheng PL, Tsai JR, Teng CLJ. Myeloperoxidase and Thyrotropin-Releasing Hormone Within Leukaemia Stem Cells Increased Chemosensitivity in Acute Myeloid Leukaemia. J Cell Mol Med 2024; 28:e70306. [PMID: 39720891 DOI: 10.1111/jcmm.70306] [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: 11/07/2023] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 12/26/2024] Open
Abstract
Leukaemia stem cells (LSCs) are major contributors to chemoresistance in acute myeloid leukaemia (AML). Identifying potential biomarkers within LSCs that can predict chemosensitivity in AML is key. This prospective study involved 20 consecutive de novo AML patients who underwent '7 + 3' induction therapy. The patients were divided into CR (n = 15) and non-CR (n = 5) groups. Using single-cell RNA sequencing, we examined the cellular states of bone marrow mononuclear cells from AML patients at diagnosis and identified LSC among these cells. Our results showed that in non-CR AML patients, a significant increase in the proportion of immature cells during haematopoiesis within the AML cell populations was observed. Moreover, the expression of myeloperoxidase (MPO) (log2 fold-change = 0.89; adjusted p < 0.0001) and thyrotropin-releasing hormone (TRH) (log2 fold-change = 0.65; adjusted p < 0.0001) was higher within LSCs in the CR group than in the non-CR group. Furthermore, patients with higher expression of MPO and TRH demonstrated improved relapse-free survival (p = 0.002 for MPO; p = 0.009 for TRH) and overall survival (p = 0.002 for MPO; p < 0.001 for TRH). The connection between MPO or TRH and chemosensitivity could be linked with the downregulation of transforming growth factor and the upregulation of interferon-α. In conclusion, MPO and TRH in LSCs could serve as chemosensitivity biomarkers in AML.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Peroxidase/metabolism
- Male
- Female
- Middle Aged
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/drug effects
- Adult
- Aged
- Drug Resistance, Neoplasm
- Biomarkers, Tumor/metabolism
- Prospective Studies
- Prognosis
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Affiliation(s)
- Chung-Hsing Chen
- Department of Mathematics, University of Taipei, Taipei, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Tsung-Chih Chen
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Ting-Shuan Wu
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
| | - Jo-Mei Maureen Chen
- Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan
| | - Chi-Ying F Huang
- Institute of Biopharmaceutical Sciences, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Po-Liang Cheng
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jia-Rung Tsai
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chieh-Lin Jerry Teng
- Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Life Science, Tunghai University, Taichung, Taiwan
- Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
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2
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Ally F, Chen X. Acute Myeloid Leukemia: Diagnosis and Evaluation by Flow Cytometry. Cancers (Basel) 2024; 16:3855. [PMID: 39594810 PMCID: PMC11592599 DOI: 10.3390/cancers16223855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
With recent technological advances and significant progress in understanding the pathogenesis of acute myeloid leukemia (AML), the updated fifth edition WHO Classification (WHO-HAEM5) and the newly introduced International Consensus Classification (ICC), as well as the European LeukemiaNet (ELN) recommendations in 2022, require the integration of immunophenotypic, cytogenetic, and molecular data, alongside clinical and morphologic findings, for accurate diagnosis, prognostication, and guiding therapeutic strategies in AML. Flow cytometry offers rapid and sensitive immunophenotyping through a multiparametric approach and is a pivotal laboratory tool for the classification of AML, identification of therapeutic targets, and monitoring of measurable residual disease (MRD) post therapy. The association of immunophenotypic features and recurrent genetic abnormalities has been recognized and applied in informing further diagnostic evaluation and immediate therapeutic decision-making. Recently, the evolving role of machine learning models in assisting flow cytometric data analysis for the automated diagnosis and prediction of underlying genetic alterations has been illustrated.
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Affiliation(s)
- Feras Ally
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA;
| | - Xueyan Chen
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA;
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
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3
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Zha C, Song J, Wan M, Lin X, He X, Wu M, Huang R. Recent advances in CAR-T therapy for the treatment of acute myeloid leukemia. Ther Adv Hematol 2024; 15:20406207241263489. [PMID: 39050113 PMCID: PMC11268017 DOI: 10.1177/20406207241263489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 06/04/2024] [Indexed: 07/27/2024] Open
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy, which has demonstrated notable efficacy against B-cell malignancies and is approved by the US Food and Drug Administration for clinical use in this context, represents a significant milestone in cancer immunotherapy. However, the efficacy of CAR-T therapy for the treatment of acute myeloid leukemia (AML) is poor. The challenges associated with the application of CAR-T therapy for the clinical treatment of AML include, but are not limited to, nonspecific distribution of AML therapeutic targets, difficulties in the production of CAR-T cells, AML blast cell heterogeneity, the immunosuppressive microenvironment in AML, and treatment-related adverse events. In this review, we summarize the recent findings regarding various therapeutic targets for AML (CD33, CD123, CLL1, CD7, etc.) and the results of the latest clinical studies on these targets. Thereafter, we also discuss the challenges related to CAR-T therapy for AML and some promising strategies for overcoming these challenges, including novel approaches such as gene editing and advances in CAR design.
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Affiliation(s)
- Chenyu Zha
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Jialu Song
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Ming Wan
- Department of Hematology, Zhujiang Hospital of Southern Medical University, No. 253 Gongyedadaozhong Road, Guangzhou, Guangdong 510282, China
| | - Xiao Lin
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaolin He
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Ming Wu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Rui Huang
- Department of Hematology, Zhujiang Hospital of Southern Medical University, No. 253 Gongyedadaozhong Road, Guangzhou, Guangdong 510282, China
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4
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Ai CJ, Chen LJ, Guo LX, Wang YP, Zhao ZY. Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction. World J Stem Cells 2024; 16:444-458. [PMID: 38690512 PMCID: PMC11056636 DOI: 10.4252/wjsc.v16.i4.444] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/11/2024] [Accepted: 03/14/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
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Affiliation(s)
- Cheng-Jin Ai
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
| | - Ling-Juan Chen
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
| | - Li-Xuan Guo
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
| | - Ya-Ping Wang
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
| | - Zi-Yi Zhao
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
- Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China.
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5
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Zhang L, Deeb G, Deeb KK, Vale C, Peker Barclift D, Papadantonakis N. Measurable (Minimal) Residual Disease in Myelodysplastic Neoplasms (MDS): Current State and Perspectives. Cancers (Basel) 2024; 16:1503. [PMID: 38672585 PMCID: PMC11048433 DOI: 10.3390/cancers16081503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Myelodysplastic Neoplasms (MDS) have been traditionally studied through the assessment of blood counts, cytogenetics, and morphology. In recent years, the introduction of molecular assays has improved our ability to diagnose MDS. The role of Measurable (minimal) Residual Disease (MRD) in MDS is evolving, and molecular and flow cytometry techniques have been used in several studies. In this review, we will highlight the evolving concept of MRD in MDS, outline the various techniques utilized, and provide an overview of the studies reporting MRD and the correlation with outcomes.
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Affiliation(s)
- Linsheng Zhang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - George Deeb
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Kristin K. Deeb
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Colin Vale
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
| | - Deniz Peker Barclift
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Nikolaos Papadantonakis
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
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6
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Vanhooren J, Dobbelaere R, Derpoorter C, Deneweth L, Van Camp L, Uyttebroeck A, De Moerloose B, Lammens T. CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them. Hemasphere 2023; 7:e937. [PMID: 37674860 PMCID: PMC10479376 DOI: 10.1097/hs9.0000000000000937] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/26/2023] [Indexed: 09/08/2023] Open
Abstract
Conventional therapies for acute myeloid leukemia (AML) are characterized by high rates of relapse, severe toxicities, and poor overall survival rates. Thus, the development of new therapeutic strategies is crucial for improving the survival and quality of life of AML patients. CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy has been extremely successful in the treatment of B-cell acute lymphoid leukemia and several mature B-cell lymphomas. However, the use of CAR T-cell therapy for AML is currently prevented due to the lack of a myeloid equivalent to CD19, as currently known cell surface targets on leukemic blasts are also expressed on healthy hematopoietic stem and progenitor cells as well as their progeny. In addition, the immunosuppressive tumor microenvironment has a dampening effect on the antitumor activity of CAR-T cells. Here, we review the therapeutic challenges limiting the use of CAR T-cell therapy for AML and discuss promising novel strategies to overcome them.
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Affiliation(s)
- Jolien Vanhooren
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
| | - Rani Dobbelaere
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
| | - Charlotte Derpoorter
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
| | - Larissa Deneweth
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
| | - Laurens Van Camp
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
| | - Anne Uyttebroeck
- Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Department of Oncology, KU Leuven, Belgium
| | - Barbara De Moerloose
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
| | - Tim Lammens
- Department of Internal Medicine and Pediatrics, Ghent University, Belgium
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Belgium
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7
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van Weelderen RE, Klein K, Harrison CJ, Jiang Y, Abrahamsson J, Arad-Cohen N, Bart-Delabesse E, Buldini B, De Moerloose B, Dworzak MN, Elitzur S, Fernández Navarro JM, Gerbing RB, Goemans BF, de Groot-Kruseman HA, Guest E, Ha SY, Hasle H, Kelaidi C, Lapillonne H, Leverger G, Locatelli F, Masetti R, Miyamura T, Norén-Nyström U, Polychronopoulou S, Rasche M, Rubnitz JE, Stary J, Tierens A, Tomizawa D, Zwaan CM, Kaspers GJ. Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol 2023; 41:2963-2974. [PMID: 36996387 PMCID: PMC10414713 DOI: 10.1200/jco.22.02120] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/22/2022] [Accepted: 02/01/2023] [Indexed: 04/01/2023] Open
Abstract
PURPOSE A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
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Affiliation(s)
- Romy E. van Weelderen
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Kim Klein
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, the Netherlands
| | - Christine J. Harrison
- Leukemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle-upon-Tyne, United Kingdom
| | - Yilin Jiang
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Jonas Abrahamsson
- Department of Pediatrics, Institute of Clinical Sciences, Salgrenska University Hospital, Gothenburg, Sweden
| | - Nira Arad-Cohen
- Pediatric Hemato-Oncology Department, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel
| | - Emmanuelle Bart-Delabesse
- IUC Toulouse-Oncopole, Laboratoire d’Hématologie secteur Génétique des Hémopathies, Toulouse, France
| | - Barbara Buldini
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Maternal and Child Health Department, Padua University, Padua, Italy
| | - Barbara De Moerloose
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Michael N. Dworzak
- St. Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, and St Anna Children's Cancer Research Institute, Vienna, Austria
| | - Sarah Elitzur
- Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center and Tel Aviv University, Tel Aviv, Israel
| | | | - Robert B. Gerbing
- Department of Statistics, The Children's Oncology Group, Monrovia, California
| | - Bianca F. Goemans
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Hester A. de Groot-Kruseman
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- DCOG, Dutch Childhood Oncology Group, Utrecht, the Netherlands
| | - Erin Guest
- Children's Mercy Kansas City, Kansas City, MO
| | - Shau-Yin Ha
- Department of Pediatrics & Adolescent Medicine, Hong Kong Children's Hospital, Kowloon, Hong Kong
| | - Henrik Hasle
- Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Charikleia Kelaidi
- Department of Pediatric Hematology and Oncology, Aghia Sophia Children's Hospital, Athens, Greece
| | - Hélène Lapillonne
- Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
| | - Guy Leverger
- Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome, Italy
| | - Riccardo Masetti
- Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy
| | - Takako Miyamura
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Sophia Polychronopoulou
- Department of Pediatric Hematology and Oncology, Aghia Sophia Children's Hospital, Athens, Greece
| | - Mareike Rasche
- Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany
| | - Jeffrey E. Rubnitz
- Department of Oncology, St Jude Children's Research Hospital, Memphis, TN
| | - Jan Stary
- Department of Pediatric Hematology and Oncology, University Hospital Motol and 2 Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Anne Tierens
- Department of Pathobiology and Laboratory Medicine, University Health Network, Toronto General Hospital, Toronto, ON, Canada
| | - Daisuke Tomizawa
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - C. Michel Zwaan
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Gertjan J.L. Kaspers
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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8
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van der Werf I, Mondala PK, Steel SK, Balaian L, Ladel L, Mason CN, Diep RH, Pham J, Cloos J, Kaspers GJL, Chan WC, Mark A, La Clair JJ, Wentworth P, Fisch KM, Crews LA, Whisenant TC, Burkart MD, Donohoe ME, Jamieson CHM. Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells. Cell Rep Med 2023; 4:100962. [PMID: 36889320 PMCID: PMC10040387 DOI: 10.1016/j.xcrm.2023.100962] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/03/2022] [Accepted: 02/10/2023] [Indexed: 03/09/2023]
Abstract
Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.
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Affiliation(s)
- Inge van der Werf
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA; Department of Hematology, Amsterdam University Medical Center, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Phoebe K Mondala
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - S Kathleen Steel
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Larisa Balaian
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Luisa Ladel
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Cayla N Mason
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Raymond H Diep
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Jessica Pham
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam University Medical Center, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gertjan J L Kaspers
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Emma Children's Hospital Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Amsterdam, the Netherlands
| | - Warren C Chan
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92037, USA
| | - Adam Mark
- Center for Computational Biology and Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92037, USA
| | - James J La Clair
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92037, USA
| | - Peggy Wentworth
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Kathleen M Fisch
- Center for Computational Biology and Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92037, USA
| | - Leslie A Crews
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Thomas C Whisenant
- Center for Computational Biology and Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92037, USA
| | - Michael D Burkart
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92037, USA
| | - Mary E Donohoe
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA
| | - Catriona H M Jamieson
- Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA.
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9
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Bachas C, Duetz C, van Spronsen MF, Verhoeff J, Garcia Vallejo JJ, Jansen JH, Cloos J, Westers TM, van de Loosdrecht AA. Characterization of myelodysplastic syndromes hematopoietic stem and progenitor cells using mass cytometry. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2023; 104:128-140. [PMID: 35289472 DOI: 10.1002/cyto.b.22066] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 02/13/2022] [Accepted: 02/28/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Myelodysplastic syndromes (MDS) at risk of transformation to acute myeloid leukemia (AML) are difficult to identify. The bone marrows of MDS patients harbor specific hematopoietic stem and progenitor cell (HSPC) abnormalities that may be associated with sub-types and risk-groups. Leukemia-associated characteristics of such cells may identify MDS patients at risk of progression to AML and provide insight in the pathobiology of MDS. METHODS Bone marrow samples from healthy donors (n = 10), low risk (n = 12) and high risk (n = 13) MDS patients were collected, in addition, AML samples for 5 out of 6 MDS patients that progressed. Mass cytometry was applied to assess expression of stem cell subset and leukemia-associated immunophenotype markers. RESULTS We analyzed the data using FlowSOM to cluster cells with similar expression of 10 commonly used stem cell markers. Metaclusters (n = 20) of these clusters represented populations of cells with a related phenotype, largely resembling known stem cell subsets. Within specific subsets, intra-cellular expression levels of pCREB, IkBα, or pS6 differed significantly between healthy bone marrow (HBM) and MDS or consecutive secondary AML samples. CD34, CD44, and CD49f expression was significantly increased in high risk MDS and AML-associated metaclusters. We identified MDS/sAML cells with aberrant phenotypes when compared to HBM. Such cells were observed in clusters of both primary MDS and secondary AML samples. CONCLUSIONS High-dimensional mass cytometry and computational data analyses enabled characterization of HSPC subsets in MDS and identification of leukemia stem cell populations based on their immunophenotype. Stem cells in MDS that display leukemia-associated features may predict the risk of developing AML.
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Affiliation(s)
- Costa Bachas
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Carolien Duetz
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Margot F van Spronsen
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jan Verhoeff
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Juan J Garcia Vallejo
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Joop H Jansen
- Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jacqueline Cloos
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Theresia M Westers
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Arjan A van de Loosdrecht
- Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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10
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Chamo M, Koren O, Goldstein O, Bujanover N, Keinan N, Scharff Y, Gazit R. Molecular Mechanisms in Murine Syngeneic Leukemia Stem Cells. Cancers (Basel) 2023; 15:cancers15030720. [PMID: 36765677 PMCID: PMC9913241 DOI: 10.3390/cancers15030720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/26/2023] Open
Abstract
Acute Myeloid Leukemia (AML) is a severe disease with a very high relapse rate. AML relapse may be attributable to leukemic stem cells (LSC). Notably, the "cancer stem cell" theory, which relates to LSCs, is controversial and criticized due to the technical peculiarities of the xenotransplant of human cells into mice. In this study, we searched for possible LSCs in an immunocompetent synergetic mice model. First, we found phenotypic heterogeneity in the ML23 leukemia line. We prospectively isolated a sub-population using the surface markers cKit+CD9-CD48+Mac1-/low, which have the potency to relapse the disease. Importantly, this sub-population can pass in syngeneic hosts and retrieve the heterogeneity of the parental ML23 leukemia line. The LSC sub-population resides in various organs. We present a unique gene expression signature of the LSC in the ML23 model compared to the other sub-populations. Interestingly, the ML23 LSC sub-population expresses therapeutic targeted genes such as CD47 and CD93. Taken together, we present the identification and molecular characterization of LSCs in a syngeneic murine model.
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11
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Lai Q, Song J, Zha J, Zheng H, Deng M, Liu Y, Lin W, Zhu Z, Zhang H, Xu B, Yang C. Microfluidic chip with reversible interface for noninvasive remission status monitoring and prognosis prediction of acute myeloid leukemia. Biosens Bioelectron 2023; 219:114803. [PMID: 36252315 DOI: 10.1016/j.bios.2022.114803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/01/2022] [Accepted: 10/09/2022] [Indexed: 11/19/2022]
Abstract
Acute myeloid leukemia (AML) requires close monitoring of remission status for timely disease management. Liquid biopsy serves as a noninvasive approach for evaluating treatment response and guiding therapeutic modifications. Herein, we designed a non-invasive Leukemic stem cell Specific Capture Chip (LSC-Chip) with reversible recognition interface for AML remission status monitoring and prognosis prediction. A stem cell marker CD34 antibody coated herringbone chip with disulfide linkers was designed to capture and release leukemic stem cells (LSCs) in peripheral blood for efficient LSC enumeration and downstream single-cell analysis. Samples from 32 AML patients and 10 healthy donors were recruited for LSC enumeration and prognosis-associated subtyping with panels of official LSC markers (CD34+/CD123+/CD38-) and (Tie2+/CD34+/CD123+/CD38-), respectively. A cutoff value of 2.5 LSCs per milliliters of peripheral blood can be used to precisely distinguish non-remission AML patients from complete remission group. Moreover, single-cell RNA-seq of LSCs was performed to check different transcriptional profiles of LSC subtypes. Overall, the LSC-Chip with reversible recognition interface enabled reliable detection of LSCs from AML patient samples for noninvasive remission status monitoring and prognosis prediction in clinical AML management.
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Affiliation(s)
- Qian Lai
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Juan Song
- Discipline of Intelligent Instrument and Equipment, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Jie Zha
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Huijian Zheng
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Manman Deng
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Yilong Liu
- The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Wei Lin
- Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China
| | - Zhi Zhu
- The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Huimin Zhang
- Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China.
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
| | - Chaoyong Yang
- Discipline of Intelligent Instrument and Equipment, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China.
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12
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An LSC-based MRD assay to complement the traditional MFC method for prediction of AML relapse: a prospective study. Blood 2022; 140:516-520. [PMID: 35613411 DOI: 10.1182/blood.2021014604] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 05/17/2022] [Indexed: 11/20/2022] Open
Abstract
Li et al delineate a novel technique for assessing measurable residual disease (MRD) by the assessment of isolated leukemia stem cells (LSCs). They report that assessment of MRD in LSCs provides a better prediction of outcome than standard multiparameter flow cytometry.
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13
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Niu J, Peng D, Liu L. Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells. Front Oncol 2022; 12:896426. [PMID: 35865470 PMCID: PMC9294245 DOI: 10.3389/fonc.2022.896426] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/06/2022] [Indexed: 12/15/2022] Open
Abstract
Acute myeloid leukemia (AML) is a polyclonal and heterogeneous hematological malignancy. Relapse and refractory after induction chemotherapy are still challenges for curing AML. Leukemia stem cells (LSCs), accepted to originate from hematopoietic stem/precursor cells, are the main root of leukemogenesis and drug resistance. LSCs are dynamic derivations and possess various elusive resistance mechanisms. In this review, we summarized different primary resistance and remolding mechanisms of LSCs after chemotherapy, as well as the indispensable role of the bone marrow microenvironment on LSCs resistance. Through a detailed and comprehensive review of the spectacle of LSCs resistance, it can provide better strategies for future researches on eradicating LSCs and clinical treatment of AML.
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Affiliation(s)
| | | | - Lingbo Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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14
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Petersen MA, Rosenberg CA, Brøndum RF, Aggerholm A, Kjeldsen E, Rahbek O, Ludvigsen M, Hasle H, Roug AS, Bill M. Immunophenotypically defined stem cell subsets in paediatric AML are highly heterogeneous and demonstrate differences in BCL-2 expression by cytogenetic subgroups. Br J Haematol 2022; 197:452-466. [PMID: 35298835 DOI: 10.1111/bjh.18094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 12/11/2022]
Abstract
In adult acute myeloid leukaemia (AML), immunophenotypic differences enable discrimination of leukaemic stem cells (LSCs) from healthy haematopoietic stem cells (HSCs). However, immunophenotypic stem cell characteristics are less explored in paediatric AML. Employing a 15-colour flow cytometry assay, we analysed the expression of eight aberrant surface markers together with BCL-2 on CD34+ CD38- bone marrow stem cells from 38 paediatric AML patients and seven non-leukaemic, age-matched controls. Furthermore, clonality was investigated by genetic analyses of sorted immunophenotypically abnormal stem cells from six patients. A total of 50 aberrant marker positive (non-HSC-like) subsets with 41 different immunophenotypic profiles were detected. CD123, CLEC12A, and IL1RAP were the most frequently expressed markers. IL1RAP, CD93, and CD25 expression were not restricted to stem cells harbouring leukaemia-associated mutations. Differential BCL-2 expression was found among defined cytogenetic subgroups. Interestingly, only immunophenotypically abnormal non-HSC-like subsets demonstrated BCL-2 overexpression. Collectively, we observed pronounced immunophenotypic heterogeneity within the stem cell compartment of paediatric AML patients. Additionally, certain aberrant markers used in adults seemed to be ineligible for detection of leukaemia-representing stem cells in paediatric patients implying that inference from adult studies must be done with caution.
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Affiliation(s)
- Marianne A Petersen
- Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Carina A Rosenberg
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rasmus F Brøndum
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
| | - Anni Aggerholm
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Eigil Kjeldsen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Ole Rahbek
- Department of Orthopaedic Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Maja Ludvigsen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Henrik Hasle
- Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anne S Roug
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marie Bill
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
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15
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Heuser M, Freeman SD, Ossenkoppele GJ, Buccisano F, Hourigan CS, Ngai LL, Tettero JM, Bachas C, Baer C, Béné MC, Bücklein V, Czyz A, Denys B, Dillon R, Feuring-Buske M, Guzman ML, Haferlach T, Han L, Herzig JK, Jorgensen JL, Kern W, Konopleva MY, Lacombe F, Libura M, Majchrzak A, Maurillo L, Ofran Y, Philippe J, Plesa A, Preudhomme C, Ravandi F, Roumier C, Subklewe M, Thol F, van de Loosdrecht AA, van der Reijden BA, Venditti A, Wierzbowska A, Valk PJM, Wood BL, Walter RB, Thiede C, Döhner K, Roboz GJ, Cloos J. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood 2021; 138:2753-2767. [PMID: 34724563 PMCID: PMC8718623 DOI: 10.1182/blood.2021013626] [Citation(s) in RCA: 420] [Impact Index Per Article: 105.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/15/2021] [Indexed: 11/20/2022] Open
Abstract
Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.
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Affiliation(s)
- Michael Heuser
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Sylvie D Freeman
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Gert J Ossenkoppele
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Francesco Buccisano
- Department of Biomedicine and Prevention, Hematology, University Tor Vergata, Rome, Italy
| | - Christopher S Hourigan
- Laboratory of Myeloid Malignancy, Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD
| | - Lok Lam Ngai
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Jesse M Tettero
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Costa Bachas
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | | | - Marie-Christine Béné
- Department of Hematology and Biology, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Veit Bücklein
- Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Anna Czyz
- Department of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland
| | - Barbara Denys
- Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University
| | - Richard Dillon
- Department of Medical and Molecular Genetics, King's College, London, United Kingdom
| | | | - Monica L Guzman
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY
| | | | | | - Julia K Herzig
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
| | | | | | | | - Francis Lacombe
- Hematology Biology, Flow Cytometry, Bordeaux University Hospital, Pessac, France
| | | | - Agata Majchrzak
- Department of Experimental Hematology, Copernicus Memorial Hospital, Lodz, Poland
| | - Luca Maurillo
- Department of Biomedicine and Prevention, Hematology, University Tor Vergata, Rome, Italy
| | - Yishai Ofran
- Department of Hematology, Shaare Zedek Medical Center Faculty of Medicine Hebrew University, Jerusalem Israel
| | - Jan Philippe
- Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University
| | - Adriana Plesa
- Department of Hematology Laboratory, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France
| | | | | | | | - Marion Subklewe
- Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Felicitas Thol
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Arjan A van de Loosdrecht
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Bert A van der Reijden
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Adriano Venditti
- Department of Biomedicine and Prevention, Hematology, University Tor Vergata, Rome, Italy
| | | | - Peter J M Valk
- Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Brent L Wood
- Department of Hematopathology, Children's Hospital Los Angeles, CA
| | - Roland B Walter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Christian Thiede
- Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany; and
- AgenDix GmbH, Dresden, Germany
| | - Konstanze Döhner
- Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
| | - Gail J Roboz
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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16
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Aung MMK, Mills ML, Bittencourt‐Silvestre J, Keeshan K. Insights into the molecular profiles of adult and paediatric acute myeloid leukaemia. Mol Oncol 2021; 15:2253-2272. [PMID: 33421304 PMCID: PMC8410545 DOI: 10.1002/1878-0261.12899] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 12/18/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a clinically and molecularly heterogeneous disease characterised by uncontrolled proliferation, block in differentiation and acquired self-renewal of hematopoietic stem and myeloid progenitor cells. This results in the clonal expansion of myeloid blasts within the bone marrow and peripheral blood. The incidence of AML increases with age, and in childhood, AML accounts for 20% of all leukaemias. Whilst there are many clinical and biological similarities between paediatric and adult AML with continuum across the age range, many characteristics of AML are associated with age of disease onset. These include chromosomal aberrations, gene mutations and differentiation lineage. Following chemotherapy, AML cells that survive and result in disease relapse exist in an altered chemoresistant state. Molecular profiling currently represents a powerful avenue of experimentation to study AML cells from adults and children pre- and postchemotherapy as a means of identifying prognostic biomarkers and targetable molecular vulnerabilities that may be age-specific. This review highlights recent advances in our knowledge of the molecular profiles with a focus on transcriptomes and metabolomes, leukaemia stem cells and chemoresistant cells in adult and paediatric AML and focus on areas that hold promise for future therapies.
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Affiliation(s)
- Myint Myat Khine Aung
- Paul O’Gorman Leukaemia Research CentreInstitute of Cancer SciencesUniversity of GlasgowUK
| | - Megan L. Mills
- Paul O’Gorman Leukaemia Research CentreInstitute of Cancer SciencesUniversity of GlasgowUK
| | | | - Karen Keeshan
- Paul O’Gorman Leukaemia Research CentreInstitute of Cancer SciencesUniversity of GlasgowUK
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17
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CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. Blood 2021; 137:1037-1049. [PMID: 33094319 DOI: 10.1182/blood.2020006921] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/30/2020] [Indexed: 12/14/2022] Open
Abstract
Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML. However, clinical and biologic characteristics of AML differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principal-component analysis. Known immunotargets of adult AML, such as IL3RA, were not overexpressed in pediatric AML compared with healthy precursors by RNA sequencing. CD33 and CLEC12A were the most upregulated immunotargets on the RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A-mutated infant AML clusters separately by RNA sequencing and overexpresses FLT3, and hence, CD33/FLT3 cotargeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSCs) and nonhematopoietic tissue, while CD33 and FLT3 are expressed on HSCs. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A and CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33 and FLT3 as immunotargets specific for KMT2A-mutated infant AML.
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18
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Niu LT, Wang YQ, Wong CCL, Gao SX, Mo XD, Huang XJ. Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage. Transl Oncol 2021; 14:101159. [PMID: 34252711 PMCID: PMC8319687 DOI: 10.1016/j.tranon.2021.101159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 06/14/2021] [Indexed: 12/13/2022] Open
Abstract
GILT is upregulated in chemoresistant LSC-enriched CD34+ progenitor cells. Inhibition of GILT in AML cells sensitized them to Ara-C treatment through ROS-mediated mitochondrial damage and apoptosis. PI3K/Akt/NRF2 pathway inhibition is critical for the intracellular oxidative state in GILT-suppression AML cells after Ara-C treatment. GILT expression is related to a poor prognosis in AML patients. The persistence of leukemia stem cells (LSCs) is one of the leading causes of chemoresistance in acute myeloid leukemia (AML). To explore the factors important in LSC-mediated resistance, we use mass spectrometry to screen the factors related to LSC chemoresistance and defined IFN-γ-inducible lysosomal thiol reductase (GILT) as a candidate. We found that the GILT expression was upregulated in chemoresistant CD34+ AML cells. Loss of function studies demonstrated that silencing of GILT in AML cells sensitized them to Ara-C treatment both in vitro and in vivo. Further mechanistic findings revealed that the ROS-mediated mitochondrial damage plays a pivotal role in inducing apoptosis of GILT-inhibited AML cells after Ara-C treatment. The inactivation of PI3K/Akt/ nuclear factor erythroid 2-related factor 2 (NRF2) pathway, causing reduced generation of antioxidants such as SOD2 and leading to a shifted ratio of GSH/GSSG to the oxidized form, contributed to the over-physiological oxidative status in the absence of GILT. The prognostic value of GILT was also validated in AML patients. Taken together, our work demonstrated that the inhibition of GILT increases AML chemo-sensitivity through elevating ROS level and induce oxidative mitochondrial damage-mediated apoptosis, and inhibition of the PI3K/Akt/NRF2 pathway enhances the intracellular oxidative state by disrupting redox homeostasis, providing a potentially effective way to overcome chemoresistance of AML.
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Affiliation(s)
- Li-Ting Niu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Yu-Qing Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871
| | - Catherine C L Wong
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871,; Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing 100191, China.; School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking University First Hospital, Beijing, 100034, China
| | - Shuai-Xin Gao
- Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing 100191, China
| | - Xiao-Dong Mo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871,.
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19
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Vanhooren J, Derpoorter C, Depreter B, Deneweth L, Philippé J, De Moerloose B, Lammens T. TARP as antigen in cancer immunotherapy. Cancer Immunol Immunother 2021; 70:3061-3068. [PMID: 34050774 PMCID: PMC8164403 DOI: 10.1007/s00262-021-02972-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022]
Abstract
In recent decades, immunotherapy has become a pivotal element in cancer treatment. A remaining challenge is the identification of cancer-associated antigens suitable as targets for immunotherapeutics with potent on-target and few off-tumor effects. The T-cell receptor gamma (TCRγ) chain alternate reading frame protein (TARP) was first discovered in the human prostate and androgen-sensitive prostate cancer. Thereafter, TARP was also identified in breast and endometrial cancers, salivary gland tumors, and pediatric and adult acute myeloid leukemia. Interestingly, TARP promotes tumor cell proliferation and migration, which is reflected in an association with worse survival. TARP expression in malignant cells, its role in oncogenesis, and its limited expression in normal tissues raised interest in its potential utility as a therapeutic target, and led to development of immunotherapeutic targeting strategies. In this review, we provide an overview of TARP expression, its role in different cancer types, and currently investigated TARP-directed immunotherapeutic options.
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Affiliation(s)
- Jolien Vanhooren
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium. .,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. .,Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
| | - Charlotte Derpoorter
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Barbara Depreter
- Department of Haematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Larissa Deneweth
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Jan Philippé
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University Hospital, Ghent, Belgium
| | - Barbara De Moerloose
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Tim Lammens
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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20
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Depreter B, De Moerloose B, Vandepoele K, Uyttebroeck A, Van Damme A, Terras E, Denys B, Dedeken L, Dresse MF, Van der Werff Ten Bosch J, Hofmans M, Philippé J, Lammens T. Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach. Pediatr Res 2021; 89:1695-1705. [PMID: 33069162 DOI: 10.1038/s41390-020-01199-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/30/2020] [Accepted: 09/25/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers. METHODS Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis. RESULTS Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast. CONCLUSION Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML. IMPACT Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
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Affiliation(s)
- Barbara Depreter
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
| | - Barbara De Moerloose
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Karl Vandepoele
- Cancer Research Institute Ghent, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Anne Uyttebroeck
- Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium
| | - An Van Damme
- Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, Brussels, Belgium
| | - Eva Terras
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Barbara Denys
- Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Laurence Dedeken
- Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, Brussels, Belgium
| | | | | | - Mattias Hofmans
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
| | - Jan Philippé
- Cancer Research Institute Ghent, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Tim Lammens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
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21
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Ngai LL, Kelder A, Janssen JJWM, Ossenkoppele GJ, Cloos J. MRD Tailored Therapy in AML: What We Have Learned So Far. Front Oncol 2021; 10:603636. [PMID: 33575214 PMCID: PMC7871983 DOI: 10.3389/fonc.2020.603636] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/16/2020] [Indexed: 12/22/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous clonal disease associated with a dismal survival, partly due to the frequent occurrence of relapse. Many patient- and leukemia-specific characteristics, such as age, cytogenetics, mutations, and measurable residual disease (MRD) after intensive chemotherapy, have shown to be valuable prognostic factors. MRD has become a rich field of research where many advances have been made regarding technical, biological, and clinical aspects, which will be the topic of this review. Since many laboratories involved in AML diagnostics have experience in immunophenotyping, multiparameter flow cytometry (MFC) based MRD is currently the most commonly used method. Although molecular, quantitative PCR based techniques may be more sensitive, their disadvantage is that they can only be applied in a subset of patients harboring the genetic aberration. Next-generation sequencing can assess and quantify mutations in many genes but currently does not offer highly sensitive MRD measurements on a routine basis. In order to provide reliable MRD results, MRD assay optimization and standardization is essential. Different techniques for MRD assessment are being evaluated, and combinations of the methods have shown promising results for improving its prognostic value. In this regard, the load of leukemic stem cells (LSC) has also been shown to add to the prognostic value of MFC-MRD. At this moment, MRD after intensive chemotherapy is most often used as a prognostic factor to help stratify patients, but also to select the most appropriate consolidation therapy. For example, to guide post-remission treatment for intermediate-risk patients where MRD positive patients receive allogeneic stem cell transplantation and MRD negative receive autologous stem cell transplantation. Other upcoming uses of MRD that are being investigated include: selecting the type of allogeneic stem cell transplantation therapy (donor, conditioning), monitoring after stem cell transplantation (to allow intervention), and determining drug efficacy for the use of a surrogate endpoint in clinical trials.
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Affiliation(s)
| | | | | | | | - Jacqueline Cloos
- Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, Vrije Universiteit, Amsterdam, Netherlands
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22
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Petersen MA, Bill M, Rosenberg CA. OMIP 072: A 15-color panel for immunophenotypic identification, quantification, and characterization of leukemic stem cells in children with acute myeloid leukemia. Cytometry A 2020; 99:382-387. [PMID: 33369057 DOI: 10.1002/cyto.a.24284] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/29/2020] [Accepted: 12/01/2020] [Indexed: 12/18/2022]
Abstract
This panel was designed to identify, quantify and phenotypically characterize putative leukemic stem cells (LSCs) in bone marrow (BM) samples from individual pediatric patients diagnosed with acute myeloid leukemia (AML). Based on an aberrant expression on immunophenotypically defined hematopoietic stem cells (HSCs), several antigens have been proposed as LSC markers in AML research, using healthy adult BM samples as reference material. Generally, these antigens have been evaluated individually in smaller panels (e.g. 8-color panels). This necessitates several tubes to characterize the LSC phenotype and compromises the ability to evaluate LSC heterogeneity. The present 15-color OMIP incorporates nine suggested LSC markers to comprehensively capture LSC immunophenotypes and to explore heterogenic marker-patterns within LSC populations in a single tube. Importantly, this single tube approach requires less input material, which is essential when sampling BM aspirates from pediatric patients where sample volumes often are sparse. As knowledge on normal expression levels of the included LSC markers in HSCs from hematologically healthy children are a prerequisite for labelling a phenotype as abnormal, we have evaluated the applicability of the panel on cryopreserved mononuclear cells (MNCs) isolated from BM samples from pediatric patients without hematological disorders as well as pediatric AML patients. The panel is optimized for cryopreserved BM MNCs, but could in principle, be utilized for LSC detection in any biological material containing human hematopoietic cells.
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Affiliation(s)
- Marianne A Petersen
- Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Marie Bill
- Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
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23
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Tan Y, Wu Q, Zhou F. Targeting acute myeloid leukemia stem cells: Current therapies in development and potential strategies with new dimensions. Crit Rev Oncol Hematol 2020; 152:102993. [PMID: 32502928 DOI: 10.1016/j.critrevonc.2020.102993] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022] Open
Abstract
High relapse rate of acute myeloid leukemia (AML) is still a crucial problem despite considerable advances in anti-cancer therapies. One crucial cause of relapse is the existence of leukemia stem cells (LSCs) with self-renewal ability, which contribute to repeated treatment resistance and recurrence. Treatments targeting LSCs, especially in combination with existing chemotherapy regimens or hematopoietic stem cell transplantation might help achieve a higher complete remission rate and improve overall survival. Many novel agents of different therapeutic strategies that aim to modulate LSCs self-renewal, proliferation, apoptosis, and differentiation are under investigation. In this review, we summarize the latest advances of different therapies in development based on the biological characteristics of LSCs, with particular attention on natural products, synthetic compounds, antibody therapies, and adoptive cell therapies that promote the LSC eradication. We also explore the causes of AML recurrence and proposed potential strategies with new dimensions for targeting LSCs in the future.
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Affiliation(s)
- Yuxin Tan
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China.
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24
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Simioni C, Bergamini F, Ferioli M, Rimondi E, Caruso L, Neri LM. New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances. Hematol Oncol 2019; 38:22-33. [PMID: 31487068 DOI: 10.1002/hon.2678] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/30/2019] [Accepted: 09/03/2019] [Indexed: 12/28/2022]
Abstract
Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi-specific T-cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)-T cells, or CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.
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Affiliation(s)
- Carolina Simioni
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Fabio Bergamini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Martina Ferioli
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Erika Rimondi
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.,LTTA-Electron Microscopy Center, University of Ferrara, Ferrara, Italy
| | - Lorenzo Caruso
- Department of Biomedical and Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.,LTTA-Electron Microscopy Center, University of Ferrara, Ferrara, Italy
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25
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Hokland P, Woll PS, Hansen MC, Bill M. The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target. Br J Haematol 2019; 187:144-156. [PMID: 31372979 DOI: 10.1111/bjh.16104] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real-time benefit for AML patients.
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Affiliation(s)
- Peter Hokland
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Petter S Woll
- Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.,Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Marcus C Hansen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Haematology, Odense University Hospital, Odense, Denmark
| | - Marie Bill
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
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26
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Depreter B, Weening KE, Vandepoele K, Essand M, De Moerloose B, Themeli M, Cloos J, Hanekamp D, Moors I, D'hont I, Denys B, Uyttebroeck A, Van Damme A, Dedeken L, Snauwaert S, Goetgeluk G, De Munter S, Kerre T, Vandekerckhove B, Lammens T, Philippé J. TARP is an immunotherapeutic target in acute myeloid leukemia expressed in the leukemic stem cell compartment. Haematologica 2019; 105:1306-1316. [PMID: 31371409 PMCID: PMC7193481 DOI: 10.3324/haematol.2019.222612] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 07/12/2019] [Indexed: 12/26/2022] Open
Abstract
Immunotherapeutic strategies targeting the rare leukemic stem cell compartment might provide salvage to the high relapse rates currently observed in acute myeloid leukemia (AML). We applied gene expression profiling for comparison of leukemic blasts and leukemic stem cells with their normal counterparts. Here, we show that the T-cell receptor γ chain alternate reading frame protein (TARP) is over-expressed in de novo pediatric (n=13) and adult (n=17) AML sorted leukemic stem cells and blasts compared to hematopoietic stem cells and normal myeloblasts (15 healthy controls). Moreover, TARP expression was significantly associated with a fms-like tyrosine kinase receptor-3 internal tandem duplication in pediatric AML. TARP overexpression was confirmed in AML cell lines (n=9), and was found to be absent in B-cell acute lymphocytic leukemia (n=5) and chronic myeloid leukemia (n=1). Sequencing revealed that both a classical TARP transcript, as described in breast and prostate adenocarcinoma, and an AML-specific alternative TARP transcript, were present. Protein expression levels mostly matched transcript levels. TARP was shown to reside in the cytoplasmic compartment and showed sporadic endoplasmic reticulum co-localization. TARP-T-cell receptor engineered cytotoxic T-cells in vitro killed AML cell lines and patient leukemic cells co-expressing TARP and HLA-A*0201. In conclusion, TARP qualifies as a relevant target for immunotherapeutic T-cell therapy in AML.
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Affiliation(s)
- Barbara Depreter
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Karin E Weening
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Karl Vandepoele
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Magnus Essand
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Barbara De Moerloose
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Maria Themeli
- Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Jacqueline Cloos
- Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Diana Hanekamp
- Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Ine Moors
- Department of Hematology, Ghent University Hospital, Ghent, Belgium
| | - Inge D'hont
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Barbara Denys
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Anne Uyttebroeck
- Department of Pediatrics, University Hospital Gasthuisberg, Louvain, Belgium
| | - An Van Damme
- Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, Brussels, Belgium
| | - Laurence Dedeken
- Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, Brussels, Belgium
| | - Sylvia Snauwaert
- Department of Hematology, AZ Sint-Jan Hospital Bruges, Bruges, Belgium
| | - Glenn Goetgeluk
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Stijn De Munter
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Tessa Kerre
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Hematology, Ghent University Hospital, Ghent, Belgium
| | - Bart Vandekerckhove
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Tim Lammens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium .,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Jan Philippé
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
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27
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Daga S, Rosenberger A, Quehenberger F, Krisper N, Prietl B, Reinisch A, Zebisch A, Sill H, Wölfler A. High GPR56 surface expression correlates with a leukemic stem cell gene signature in CD34-positive AML. Cancer Med 2019; 8:1771-1778. [PMID: 30848055 PMCID: PMC6488118 DOI: 10.1002/cam4.2053] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/24/2019] [Accepted: 02/04/2019] [Indexed: 12/11/2022] Open
Abstract
Acute myeloid leukemia (AML) is driven by a minor fraction of leukemic stem cells (LSCs) whose persistence is considered being the primary cause of disease relapse. A detailed characterization of the surface immunophenotype of LSCs to discriminate them from bulk leukemic blasts may enable successful targeting of this population thereby improving patient outcomes in AML. To identify surface markers, which may reflect LSC activity at diagnosis, we performed a detailed analysis of 16 putative LSC markers in CD34/38 leukemic subcompartments of 150 diagnostic AML samples using multicolor flow cytometry. The most promising markers were then selected to determine a possible correlation of their expression with a recently published LSC gene signature. We found GPR56 and CLL-1 to be the most prominently differently expressed surface markers in AML subcompartments. While GPR56 was highest expressed within the LSC-enriched CD34+ 38- subcompartment as compared to CD34+ 38+ and CD34- leukemic bulk cells, CLL-1 expression was lowest in CD34+ 38- leukemic cells and increased in CD34+ 38+ and CD34- blasts. Furthermore, high GPR56 surface expression in CD34+ 38- leukemic cells correlated with a recently published LSC gene expression signature and was associated with decreased overall survival in patients receiving intensive chemotherapy. In contrast, CLL-1 expression correlated inversely with the LSC gene signature and was not informative on outcome. Our data strongly support GPR56 as a promising clinically relevant marker for identifying leukemic cells with LSC activity at diagnosis in CD34-positive AML.
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Affiliation(s)
- Shruti Daga
- Division of Hematology, Medical University of Graz, Graz, Austria.,CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Angelika Rosenberger
- Division of Hematology, Medical University of Graz, Graz, Austria.,CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Franz Quehenberger
- Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Nina Krisper
- CBmed Center of Biomarker Research in Medicine, Graz, Austria
| | - Barbara Prietl
- CBmed Center of Biomarker Research in Medicine, Graz, Austria.,Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Andreas Reinisch
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Armin Zebisch
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Heinz Sill
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Albert Wölfler
- Division of Hematology, Medical University of Graz, Graz, Austria.,CBmed Center of Biomarker Research in Medicine, Graz, Austria
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28
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The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia. Leukemia 2018; 33:348-357. [PMID: 30089916 DOI: 10.1038/s41375-018-0227-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/20/2018] [Accepted: 07/10/2018] [Indexed: 01/24/2023]
Abstract
Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64-6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38-8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63-7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16-7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.
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29
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Kerage D, Soon MSF, Doff BL, Kobayashi T, Nissen MD, Lam PY, Leggatt GR, Mattarollo SR. Therapeutic vaccination with 4-1BB co-stimulation eradicates mouse acute myeloid leukemia. Oncoimmunology 2018; 7:e1486952. [PMID: 30288351 DOI: 10.1080/2162402x.2018.1486952] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 12/17/2022] Open
Abstract
Immunomodulatory therapies can effectively control haematological malignancies. Previously we reported the effectiveness of combination immunotherapies that centre on 4-1BB-targeted co-stimulation of CD8 + T cells, particularly when simultaneously harnessing the immune adjuvant properties of Natural Killer T (NKT) cells. The objective of this study was to assess the effectiveness of agonistic anti-4-1BB antibody-based combination therapy against two aggressive forms of acute myeloid leukemia (AML). Anti-4-1BB treatment alone resulted in transient suppression of established AML-ETO9a tumor growth in 50% of mice, however the majority of these mice subsequently succumbed to disease. Combining alpha-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with anti-4-1BB antibody treatment increased the proportion of responding mice to 100%, and protection led to long-term, tumor-free survival, demonstrating complete eradication of AML. This finding was extended to established mixed lymphocytic leukemia (MLL)-AF9 tumors, whereby vaccine plus anti-4-1BB combination similarly resulted in 100% protection. The addition of anti-PD-1 to anti-4-1BB treatment, although improving survival outcomes compared to anti-4-1BB alone, was not as effective as NKT cell vaccination. The effectiveness of 4-1BB combination therapies was dependent on IFN-γ signaling within host cells, but not tumors. Vaccine plus anti-4-1BB therapy elicited potent generation of functional effector and memory CD8 + T cells in all tumor-associated organs. Therapy induced KLRG1+ effector CD8 T cells were the most effective at controlling disease. We show that combining NKT cell-targeting vaccination with anti-4-1BB provides excellent therapeutic responses against AML and MLL in mice, and these results will guide ongoing efforts in finding immunotherapeutic solutions against acute myeloid leukemias.
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Affiliation(s)
- Daniel Kerage
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Megan S F Soon
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Brianna L Doff
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Takumi Kobayashi
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Michael D Nissen
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Pui Yeng Lam
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Graham R Leggatt
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Stephen R Mattarollo
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia
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30
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Klein K, de Haas V, Kaspers GJL. Clinical challenges in de novo pediatric acute myeloid leukemia. Expert Rev Anticancer Ther 2018; 18:277-293. [DOI: 10.1080/14737140.2018.1428091] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Kim Klein
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Valérie de Haas
- Dutch Childhood Oncology Group, The Hague, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Gertjan J. L. Kaspers
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
- Dutch Childhood Oncology Group, The Hague, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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