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Nat Med. 2016 Dec;22(12):1488-1495. doi: 10.1038/nm.4210. Epub 2016 Nov 14.

DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
4
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
7
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
8
Diagnostic Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
10
Irving Cancer Research Center, Columbia University, New York, New York, USA.
11
Division of Hematology and Hemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
12
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13
Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, New York, USA.
14
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
15
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
16
Christian Doppler Laboratory for Chemical Genetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
17
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
18
Department of Oncology, Montefiore Medical Center, Bronx, New York, USA.

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 DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3AR882 cells 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 DNMT3AR882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3AR882 cells 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 DNMT3AR882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.

PMID:
27841873
PMCID:
PMC5359771
DOI:
10.1038/nm.4210
[Indexed for MEDLINE]
Free PMC Article

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