Journal Article

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

Krivtsov, Andrei V, Kubicek, Stefan, Tovbin, Daniel, Rowe, Jacob M, Luciani, Luisa, Bastian, Lennart, Rivera, Sharon A, Gonzalez, Adriana Rodriguez, Ganzel, Chezi, Keller, Matthew D, Loizou, Evangelia, Staber, Philipp B, Mohanty, Abhinita, Chramiec, Alan G, Levine, Ross L, Abdel-Wahab, Omar, Armstrong, Scott A, Nimer, Stephen D, Sperr, Wolfgang R, Shank, Kaitlyn, Guryanova, Olga A, Arcila, Maria E, Tallman, Martin S, Garrett-Bakelman, Francine E, Cross, Justin R, Gönen, Mithat, Hoermann, Gregor, Koche, Richard P, Pastore, Friederike, Melnick, Ari M, Mukherjee, Siddhartha, Paietta, Elisabeth M, Durham, Benjamin H, Spitzer, Barbara, Pronier, Elodie, McKenney, Anna Sophia, Weinstein, Abby R, Lieu, Yen K, Mason, Christopher E

2016

Overview

AML cells carrying R882 mutations in DNMT3A fail to sense and repair DNA damage induced by standard-dose chemotherapy as a result of impaired chromatin remodeling 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 ( DNMT3A R882 ), have been observed in AML 1 , 2 , 3 and in individuals with clonal hematopoiesis in the absence of leukemic transformation 4 , 5 . Patients with DNMT3A R882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy 6 , 7 , suggesting that DNMT3A R882 cells persist and drive relapse 8 . We found that Dnmt3a mutations induced hematopoietic stem cell expansion, cooperated with mutations in the FMS-like tyrosine kinase 3 gene ( Flt3 ITD ) and the nucleophosmin gene ( Npm1 c ) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3A R882 mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3A R882 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 DNMT3A R882 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059/2326 / 631/67/1990/283/1897 / 631/67/70 / 631/67/71 / Acute myelocytic leukemia / Animals / Anthracyclines / Anthracyclines - therapeutic use / Antineoplastic Agents - therapeutic use / Biomedicine / Cancer Research / Cell Line, Tumor / Cell Proliferation - genetics / Cell Survival / Chemotherapy / Chromatin Assembly and Disassembly - genetics / Daunorubicin - therapeutic use / Deoxyribonucleic acid / DNA / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA Methyltransferase 3A / Dosage and administration / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / fms-Like Tyrosine Kinase 3 - genetics / Gene mutation / Genetic aspects / Hematopoietic Stem Cells / Humans / Immunoblotting / Immunoprecipitation / Infectious Diseases / letter / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Mass Spectrometry / Metabolic Diseases / Methyltransferases / Mice / Molecular Medicine / Mutation / Neurosciences / Nuclear Proteins - genetics / Nucleophosmin / Nucleosomes - metabolism / Stem cells