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

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

Research output: Contribution to journalArticle

86 Scopus citations

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 (DNMT3A R882), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3A R882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3A R882 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 (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.

Original languageEnglish (US)
Pages (from-to)1488-1495
Number of pages8
JournalNature Medicine
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Guryanova, O. A., Shank, K., Spitzer, B., Luciani, L., Koche, R. P., Garrett-Bakelman, F. E., Ganzel, C., Durham, B. H., Mohanty, A., Hoermann, G., Rivera, S. A., Chramiec, A. G., Pronier, E., Bastian, L., Keller, M. D., Tovbin, D., Loizou, E., Weinstein, A. R., Gonzalez, A. R., ... Levine, R. L. (2016). DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nature Medicine, 22(12), 1488-1495. https://doi.org/10.1038/nm.4210