title: DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
abstract: Although the majority of patients with acute myeloid leukemia (AML) initially respond to chemotherapy, many of them subsequently relapse, and the mechanistic basis for AML persistence following chemotherapy has not been determined. Recurrent somatic mutations in DNA methyltransferase 3A (DNMT3A), most frequently at arginine 882 (DNMT3AR882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3AR882AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882cells persist and drive relapse. We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene (Flt3ITD) and the nucleophosmin gene (Npm1c) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3AR882mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882cells showed impaired nucleosome eviction and chromatin remodeling in response to anthracycline treatment, which resulted from attenuated recruitment of histone chaperone SPT-16 following anthracycline exposure. This defect led to an inability to sense and repair DNA torsional stress, which resulted in increased mutagenesis. Our findings identify a crucial role for DNMT3AR882mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Guryanova
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shank
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Luciani
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Koche
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Francine E
authors.initials: FE
authors.lastname: Garrett-Bakelman
authors.affiliation: Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Chezi
authors.initials: C
authors.lastname: Ganzel
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Durham
authors.affiliation: Diagnostic Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Abhinita
authors.initials: A
authors.lastname: Mohanty
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Rivera
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Chramiec
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pronier
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bastian
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tovbin
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Loizou
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Abby R
authors.initials: AR
authors.lastname: Weinstein
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Adriana Rodriguez
authors.initials: AR
authors.lastname: Gonzalez
authors.affiliation: Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Yen K
authors.initials: YK
authors.lastname: Lieu
authors.affiliation: Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Friederike
authors.initials: F
authors.lastname: Pastore
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Anna Sophia
authors.initials: AS
authors.lastname: McKenney
authors.affiliation: Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrei V
authors.identifier: 0000-0002-5511-1686
authors.initials: AV
authors.lastname: Krivtsov
authors.affiliation: Division of Hematology and Hemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Christopher E
authors.identifier: 0000-0002-1850-1642
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Diagnostic Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Christian Doppler Laboratory for Chemical Genetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.identifier: 0000-0003-0855-8343
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: Division of Hematology and Hemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Philipp B
authors.initials: PB
authors.lastname: Staber
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Paietta
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D003630:Daunorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006412:Hematopoietic Stem Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D009707:Nucleosomes / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D009707:Nucleosomes; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051941:fms-Like Tyrosine Kinase 3; D003630:Daunorubicin