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

Nature Medicine volume 22, pages 1488–1495 (2016)Cite this article

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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 AML1,2,3 and in individuals with clonal hematopoiesis in the absence of leukemic transformation4,5. Patients with DNMT3AR882 AML have an inferior outcome when treated with standard-dose daunorubicin-based induction chemotherapy6,7, suggesting that DNMT3AR882 cells persist and drive relapse8. 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.

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Figure 1: Dnmt3aR878H mutation augments HSC function and cooperates with co-occurring AML disease alleles in vivo.
Figure 2: Expression of mutant DNMT3A leads to anthracycline resistance.
Figure 3: Cells with mutant DNMT3A have a DNA damage signaling defect in response to anthracyclines.
Figure 4: Expression of mutant DNMT3A impairs chromatin remodeling in response to DNA distortion.

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Acknowledgements

The authors are grateful to A. Ringler, C. Sheridan, J. Gandara and Y. Neelamraju for technical support; to Weill Cornell Medicine Epigenomics Core for sequencing services; to H. Erdjument-Bromage for assistance with proteomics; to S. Zha (Columbia University Medical Center); and to A. Ciccia (Columbia University Medical Center) for critical reading of the manuscript and helpful suggestions. cDNA encoding human wild-type DNMT3A was a kind gift from F. Fuks (Free University of Brussels). This work was supported by NCI K99 grant CA178191 and Lauri Strauss Leukemia Foundation award to O.A.G.; by NCI K08 grant CA169055 and an American Society of Hematology (ASHAMFDP-20121) under the ASH-AMFDP partnership with The Robert Wood Johnson Foundation to F.E.G.-B.; by a Hyundai Hope On Wheels award to B.S.; by a Gabrielle's Angel Fund grant to R.L.L. and A.M.M.; by NCI grant CA172636 to R.L.L. and A.M.M.; by the Samuel Waxman Cancer Research Center; by a Stand Up To Cancer Convergence Award to R.L.L; and the NCI U10 grant CA180827 to E.M.P., R.L.L. and A.M.M. A.S.M. is supported by NIH grants T32GM007739 and F30CA18349. A.M.M. is a Burroughs Wellcome Clinical Translational Scholar, and is supported by the Sackler Center for Biomedical and Physical Sciences. R.L.L. is a LLS Scholar. P.B.S. is supported by the Austrian Research Foundation (#P27132) and the Oesterreichische Nationalbank (OeNB) Anniversary Fund (#15936). MSKCC cores used in these studies are supported by the P30 Core Grant CA008748. A part of this study was coordinated by the ECOG-ACRIN Cancer Research Group (R.L. Comis and M.D. Schnall) and supported in part by Public Health Service Grants CA180820, CA180794, CA180791, CA189859, CA180827 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Olga A Guryanova, Kaitlyn Shank, Benjamin H Durham, Elodie Pronier, Lennart Bastian, Matthew D Keller, Daniel Tovbin, Abby R Weinstein, Adriana Rodriguez Gonzalez, Friederike Pastore, Anna Sophia McKenney, Omar Abdel-Wahab & Ross L Levine

  2. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Barbara Spitzer & Scott A Armstrong

  3. University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA

    Luisa Luciani & Stephen D Nimer

  4. Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Richard P Koche, Alan G Chramiec, Andrei V Krivtsov, Scott A Armstrong & Ross L Levine

  5. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Richard P Koche, Evangelia Loizou & Scott A Armstrong

  6. Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA

    Francine E Garrett-Bakelman & Ari M Melnick

  7. Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel

    Chezi Ganzel & Jacob M Rowe

  8. Diagnostic Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Abhinita Mohanty & Maria E Arcila

  9. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Gregor Hoermann

  10. Irving Cancer Research Center, Columbia University, New York, New York, USA

    Sharon A Rivera, Yen K Lieu & Siddhartha Mukherjee

  11. Division of Hematology and Hemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria

    Wolfgang R Sperr & Philipp B Staber

  12. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Justin R Cross

  13. Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, New York, USA

    Christopher E Mason

  14. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Martin S Tallman, Omar Abdel-Wahab & Ross L Levine

  15. Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Omar Abdel-Wahab & Ross L Levine

  16. Christian Doppler Laboratory for Chemical Genetics and Anti-Infectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Stefan Kubicek

  17. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Mithat Gönen

  18. Department of Oncology, Montefiore Medical Center, Bronx, New York, USA

    Elisabeth M Paietta

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  1. Olga A Guryanova
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Contributions

O.A.G. and K.S. performed most of the experiments. L.B., M.D.K., D.T., E.L., A.R.W., A.R.G., E.P., F.P. and A.S.M. assisted with many of the experiments. C.Z., J.M.R., M.S.T., O.A.-W., M.G., E.M.P., A.M.M. and R.L.L. designed the clinical study, and collected and analyzed patient data. A.G.C., A.V.K., R.P.K. and S.A.A. designed, conducted and analyzed ChIP-sequencing experiments. B.S., F.E.G.-B. and A.M.M. assisted with RNA-sequencing, ERRBS and data analysis. B.S. mined TCGA data. L.L. and S.D.N. designed and performed peptide pull-down assay. B.H.D. assisted with animal hematopathology. A.M. and M.E.A. assisted with patient DNA re-sequencing. G.H., W.R.S., S.K. and P.B.S. designed and conducted ex vivo drug studies on primary AML samples. J.R.C. designed and oversaw small-molecule quantification by mass-spectroscopy. S.A.R., Y.K.L. and S.M. provided Dnmt3a cKO mice, S.M. contributed to study conception. O.A.-W. assisted with study design. O.A.G. and R.L.L. conceived the study, designed experiments, analyzed data and wrote the manuscript. All of the authors read, edited and approved the manuscript.

Corresponding authors

Correspondence to Siddhartha Mukherjee or Ross L Levine.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–3, 7, 8 (PDF 15780 kb)

Supplementary Table 4

Differentially methylated cytosines (DMCs) in LSK cells from Dnmt3amut mice compared to wild-type controls, identified by MethyKit (XLSX 1235 kb)

Supplementary Table 5

Differentially expressed genes in LSK cells from Dnmt3amut mice compared to wild-type controls, identified by RNA-seq. (XLSX 58 kb)

Supplementary Table 6

Candidate DNMT3A interacting proteins identified by mass-spectroscopy following DNMT3A peptide pull-down. (XLSX 56 kb)

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Guryanova, O., Shank, K., Spitzer, B. et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22, 1488–1495 (2016). https://doi.org/10.1038/nm.4210

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