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. Lieu & 19 others Jacob 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

59 Citations (Scopus)

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

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Nucleosomes
Anthracyclines
Acute Myeloid Leukemia
Chemotherapy
Mutation
Drug Therapy
Chromatin Assembly and Disassembly
Chromatin
Histone Chaperones
Genes
Mutagenesis
Daunorubicin
Recurrence
Induction Chemotherapy
DNA methyltransferase 3A
Stem cells
Hematopoiesis
Residual Neoplasm
Torsional stress
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Guryanova, O. A., Shank, K., Spitzer, B., Luciani, L., Koche, R. P., Garrett-Bakelman, F. E., ... 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

DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. / Guryanova, Olga A.; Shank, Kaitlyn; Spitzer, Barbara; Luciani, Luisa; Koche, Richard P.; Garrett-Bakelman, Francine E.; Ganzel, Chezi; Durham, Benjamin H.; Mohanty, Abhinita; Hoermann, Gregor; Rivera, Sharon A.; Chramiec, Alan G.; Pronier, Elodie; Bastian, Lennart; Keller, Matthew D.; Tovbin, Daniel; Loizou, Evangelia; Weinstein, Abby R.; Gonzalez, Adriana Rodriguez; Lieu, Yen K.; Rowe, Jacob M.; Pastore, Friederike; McKenney, Anna Sophia; Krivtsov, Andrei V.; Sperr, Wolfgang R.; Cross, Justin R.; Mason, Christopher E.; Tallman, Martin S.; Arcila, Maria E.; Abdel-Wahab, Omar; Armstrong, Scott A.; Kubicek, Stefan; Staber, Philipp B.; Gönen, Mithat; Paietta, Elisabeth M.; Melnick, Ari M.; Nimer, Stephen D.; Mukherjee, Siddhartha; Levine, Ross L.

In: Nature Medicine, Vol. 22, No. 12, 01.12.2016, p. 1488-1495.

Research output: Contribution to journalArticle

Guryanova, OA, Shank, K, Spitzer, B, Luciani, L, Koche, RP, Garrett-Bakelman, FE, Ganzel, C, Durham, BH, Mohanty, A, Hoermann, G, Rivera, SA, Chramiec, AG, Pronier, E, Bastian, L, Keller, MD, Tovbin, D, Loizou, E, Weinstein, AR, Gonzalez, AR, Lieu, YK, Rowe, JM, Pastore, F, McKenney, AS, Krivtsov, AV, Sperr, WR, Cross, JR, Mason, CE, Tallman, MS, Arcila, ME, Abdel-Wahab, O, Armstrong, SA, Kubicek, S, Staber, PB, Gönen, M, Paietta, EM, Melnick, AM, Nimer, SD, Mukherjee, S & Levine, RL 2016, 'DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling', Nature Medicine, vol. 22, no. 12, pp. 1488-1495. https://doi.org/10.1038/nm.4210
Guryanova OA, Shank K, Spitzer B, Luciani L, Koche RP, Garrett-Bakelman FE et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nature Medicine. 2016 Dec 1;22(12):1488-1495. https://doi.org/10.1038/nm.4210
Guryanova, Olga A. ; Shank, Kaitlyn ; Spitzer, Barbara ; Luciani, Luisa ; Koche, Richard P. ; Garrett-Bakelman, Francine E. ; Ganzel, Chezi ; Durham, Benjamin H. ; Mohanty, Abhinita ; Hoermann, Gregor ; Rivera, Sharon A. ; Chramiec, Alan G. ; Pronier, Elodie ; Bastian, Lennart ; Keller, Matthew D. ; Tovbin, Daniel ; Loizou, Evangelia ; Weinstein, Abby R. ; Gonzalez, Adriana Rodriguez ; Lieu, Yen K. ; Rowe, Jacob M. ; Pastore, Friederike ; McKenney, Anna Sophia ; Krivtsov, Andrei V. ; Sperr, Wolfgang R. ; Cross, Justin R. ; Mason, Christopher E. ; Tallman, Martin S. ; Arcila, Maria E. ; Abdel-Wahab, Omar ; Armstrong, Scott A. ; Kubicek, Stefan ; Staber, Philipp B. ; Gönen, Mithat ; Paietta, Elisabeth M. ; Melnick, Ari M. ; Nimer, Stephen D. ; Mukherjee, Siddhartha ; Levine, Ross L. / DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. In: Nature Medicine. 2016 ; Vol. 22, No. 12. pp. 1488-1495.
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AU - Koche, Richard P.

AU - Garrett-Bakelman, Francine E.

AU - Ganzel, Chezi

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AU - Arcila, Maria E.

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AU - Armstrong, Scott A.

AU - Kubicek, Stefan

AU - Staber, Philipp B.

AU - Gönen, Mithat

AU - Paietta, Elisabeth M.

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