TitleDNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
Publication TypeJournal Article
Year of Publication2016
AuthorsGuryanova, 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, and Levine Ross L.
JournalNat Med
Volume22
Issue12
Pagination1488-1495
Date Published2016 12
ISSN1546-170X
KeywordsAnimals, Anthracyclines, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Chromatin Assembly and Disassembly, Daunorubicin, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Drug Resistance, Neoplasm, fms-Like Tyrosine Kinase 3, Hematopoietic Stem Cells, Humans, Immunoblotting, Immunoprecipitation, Leukemia, Myeloid, Acute, Mass Spectrometry, Mice, Mutation, Nuclear Proteins, Nucleophosmin, Nucleosomes
Abstract

<p>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), have been observed in AML and in individuals with clonal hematopoiesis in the absence of leukemic transformation. Patients with DNMT3A AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy, suggesting that DNMT3A 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) and the nucleophosmin gene (Npm1) to induce AML in vivo, and promoted resistance to anthracycline chemotherapy. In patients with AML, the presence of DNMT3A mutations predicts minimal residual disease, underscoring their role in AML chemoresistance. DNMT3A 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 mutations in driving AML chemoresistance and highlight the importance of chromatin remodeling in response to cytotoxic chemotherapy.</p>

DOI10.1038/nm.4210
Alternate JournalNat Med
PubMed ID27841873
PubMed Central IDPMC5359771
Grant ListK08 CA169055 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
R00 CA178191 / CA / NCI NIH HHS / United States
UG1 CA189859 / CA / NCI NIH HHS / United States
U10 CA180791 / CA / NCI NIH HHS / United States
R01 CA169784 / CA / NCI NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P 27132 / FWF_ / Austrian Science Fund FWF / Austria
U10 CA180794 / CA / NCI NIH HHS / United States
K99 CA178191 / CA / NCI NIH HHS / United States
K12 CA184746 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
F30 CA183497 / CA / NCI NIH HHS / United States