WT1 and DNMT3A Play Essential Roles in the Growth of Certain Patient AML Cells in Mice

Letter to Blood| February 23, 2023 WT1 and DNMT3A play essential roles in the growth of certain patient AML cells in mice Maryam Ghalandary, Maryam Ghalandary ∗ Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Yuqiao Gao, Yuqiao Gao ∗ Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Diana Amend, Diana Amend Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Ginte Kutkaite, Ginte Kutkaite Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, GermanyDepartment of Biology, Ludwig-Maximilians University Munich, Martinsried, Germany https://orcid.org/0000-0002-2918-294X Search for other works by this author on: This Site PubMed Google Scholar Binje Vick, Binje Vick Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, GermanyGerman Cancer Consortium, Partner Site Munich, Munich, Germany https://orcid.org/0000-0003-1956-2778 Search for other works by this author on: This Site PubMed Google Scholar Karsten Spiekermann, Karsten Spiekermann Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany https://orcid.org/0000-0002-5139-4957 Search for other works by this author on: This Site PubMed Google Scholar Maja Rothenberg-Thurley, Maja Rothenberg-Thurley Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Klaus H. Metzeler, Klaus H. Metzeler Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, GermanyDepartment of Hematology and Cell Therapy, University Hospital Leipzig, Leipzig, Germany https://orcid.org/0000-0003-3920-7490 Search for other works by this author on: This Site PubMed Google Scholar Anetta Marcinek, Anetta Marcinek Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Marion Subklewe, Marion Subklewe Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, Ludwig Maximilians University, Munich, Germany https://orcid.org/0000-0003-3905-0251 Search for other works by this author on: This Site PubMed Google Scholar Michael P. Menden, Michael P. Menden Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, GermanyDepartment of Biology, Ludwig-Maximilians University Munich, Martinsried, GermanyGerman Centre for Diabetes Research, Neuherberg, Germany https://orcid.org/0000-0003-0267-5792 Search for other works by this author on: This Site PubMed Google Scholar Vindi Jurinovic, Vindi Jurinovic Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany Search for other works by this author on: This Site PubMed Google Scholar Ehsan Bahrami, Ehsan Bahrami Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany https://orcid.org/0000-0002-1672-5503 Search for other works by this author on: This Site PubMed Google Scholar Irmela Jeremias Irmela Jeremias Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, GermanyGerman Cancer Consortium, Partner Site Munich, Munich, GermanyDepartment of Pediatrics, University Hospital, Ludwig Maximilians University, Munich, Germany https://orcid.org/0000-0003-1773-7677 Search for other works by this author on: This Site PubMed Google Scholar Blood (2023) 141 (8): 955–960. https://doi.org/10.1182/blood.2022016411 Article history Submitted: March 23, 2022 Accepted: September 25, 2022 Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Maryam Ghalandary, Yuqiao Gao, Diana Amend, Ginte Kutkaite, Binje Vick, Karsten Spiekermann, Maja Rothenberg-Thurley, Klaus H. Metzeler, Anetta Marcinek, Marion Subklewe, Michael P. Menden, Vindi Jurinovic, Ehsan Bahrami, Irmela Jeremias; WT1 and DNMT3A play essential roles in the growth of certain patient AML cells in mice. Blood 2023; 141 (8): 955–960. doi: https://doi.org/10.1182/blood.2022016411 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Myeloid Neoplasia TO THE EDITOR: Patients with acute myeloid leukemia (AML) experience poor prognosis, and precision oncology represents an attractive therapeutic option, applying targeted therapies against so-called dependencies.1-4 Dependencies are essential components required for cell growth and survival; they represent attractive therapeutic targets as their inhibition reduces tumor burden.1-4 Many genes recurrently mutated in AML contribute to oncogenesis,5,6 which may imply a role as dependency and allow precision therapy, based on genetic profiling. Examples already in routine clinical practice include AML with mutated FMS related receptor tyrosine kinase 3 treated with midostaurin and AML with mutated isocitrate dehydrogenase responding to ivosidenib.2 Herein, we asked whether additional recurrently mutated genes might represent dependencies in established AML. Previous efforts to identify dependencies used established cell lines, including large-scale functional genomic screens; WT1 and DNMT3A were shown to be dispensable... References 1.Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11(2):41.Google ScholarCrossrefSearch ADS PubMed 2.Short NJ, Konopleva M, Kadia TM, et al. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 2020;10(4):506-525.Google ScholarCrossrefSearch ADS PubMed 3.Park JJH, Hsu G, Siden EG, Thorlund K, Mills EJ. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J Clin. 2020;70(2):125-137.Google ScholarCrossrefSearch ADS PubMed 4.Lin A, Sheltzer JM. Discovering and validating cancer genetic dependencies: approaches and pitfalls. Nat Rev Genet. 2020;21(11):671-682.Google ScholarCrossrefSearch ADS PubMed 5.Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686-698.Google ScholarCrossrefSearch ADS PubMed 6.Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058-1066.Google ScholarCrossrefSearch ADS 7.Dempster JM, Pacini C, Pantel S, et al. Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets. Nat Commun. 2019;10(1):5817.Google ScholarCrossrefSearch ADS PubMed 8.Ben-David U, Siranosian B, Ha G, et al. Genetic and transcriptional evolution alters cancer cell line drug response. Nature. 2018;560(7718):325-330.Google ScholarCrossrefSearch ADS PubMed 9.Unger C, Kramer N, Walzl A, Scherzer M, Hengstschlager M, Dolznig H. Modeling human carcinomas: physiologically relevant 3D models to improve anti-cancer drug development. Adv Drug Deliv Rev. 2014;79-80:50-67.Google ScholarCrossrefSearch ADS PubMed 10.Woo XY, Giordano J, Srivastava A, et al. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat Genet. 2021;53(1):86-99.Google ScholarCrossrefSearch ADS PubMed 11.Ben-David U, Beroukhim R, Golub TR. Genomic evolution of cancer models: perils and opportunities. Nat Rev Cancer. 2019;19(2):97-109.Google ScholarCrossrefSearch ADS PubMed 12.Vick B, Rothenberg M, Sandhofer N, et al. An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging. PLoS One. 2015;10(3):e0120925.Google ScholarCrossrefSearch ADS PubMed 13.Bahrami E, Becker M, Wirth AK, et al. A CRISPR/Cas9 library screen in patients’ leukemia cells in vivo [abstract]. Blood. 2019;134(suppl 1). Abstract 3945.Google Scholar 14.Li W, Xu H, Xiao T, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15(12):554.Google ScholarCrossrefSearch ADS PubMed 15.Asimgil H, Ertetik U, Cevik NC, et al. Targeting the undruggable oncogenic KRAS: the dawn of hope. JCI Insight. 2022;7(1):e153688.Google ScholarCrossrefSearch ADS PubMed 16.Wang T, Yu H, Hughes NW, et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell. 2017;168(5):890-903.e815.Google ScholarCrossrefSearch ADS PubMed 17.Lin S, Scheideggar NK, et al. An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML. Cancer Discov. 2022;12(2):432-449.Google ScholarCrossrefSearch ADS PubMed 18.Liu WH, Mrozek-Gorska P, Wirth AK, et al. Inducible transgene expression in PDX models in vivo identifies KLF4 as a therapeutic target for B-ALL. Biomark Res. 2020;8:46.Google ScholarCrossrefSearch ADS PubMed 19.Rampal R, Figueroa ME. Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica. 2016;101(6):672-679.Google ScholarCrossrefSearch ADS PubMed 20.Pronier E, Bowman RL, Ahn J, et al. Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis. Blood. 2018;132(12):1265-1278.Google ScholarCrossrefSearch ADS PubMed 21.Mayle A, Yang L, Rodriguez B, et al. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood. 2015;125(4):629-638.Google ScholarCrossrefSearch ADS PubMed 22.Celik H, Mallaney C, Kothari A, et al. Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. Blood. 2015;125(4):619-628.Google ScholarCrossrefSearch ADS PubMed 23.Huang YH, Chen CW, Sundaramurthy V, et al. Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor. Cancer Discov. 2022;12(1):220-235.Google ScholarCrossrefSearch ADS PubMed 24.Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011;44(1):23-31.Google ScholarCrossrefSearch ADS PubMed 25.Bera R, Chiu MC, Huang YJ, Huang G, Lee YS, Shih LY. DNMT3A mutants provide proliferating advantage with augmentation of self-renewal activity in the pathogenesis of AML in KMT2A-PTD-positive leukemic cells. Oncogenesis. 2020;9(2):7.Google ScholarCrossrefSearch ADS PubMed © 2023 by The American Society of Hematology2023 © 2023 by The American Society of Hematology2023 You do not currently have access to this content. Sign in via your Institution