DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

Liubin Yang, Benjamin Rodriguez, Allison Mayle, Hyun Jung Park, Xueqiu Lin, Min Luo, Mira Jeong, Choladda V. Curry, Sang Bae Kim, David Ruau, Xiaotian Zhang, Ting Zhou, Michael Zhou, Vivienne I. Rebel, Grant A. Challen, Berthold Göttgens, Ju Seog Lee, Rachel Rau, Wei Li, Margaret A. Goodell

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Abstract

DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Original languageEnglish (US)
Pages (from-to)922-934
Number of pages13
JournalCancer Cell
Volume29
Issue number6
DOIs
StatePublished - Jun 13 2016

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Yang, L., Rodriguez, B., Mayle, A., Park, H. J., Lin, X., Luo, M., Jeong, M., Curry, C. V., Kim, S. B., Ruau, D., Zhang, X., Zhou, T., Zhou, M., Rebel, V. I., Challen, G. A., Göttgens, B., Lee, J. S., Rau, R., Li, W., & Goodell, M. A. (2016). DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias. Cancer Cell, 29(6), 922-934. https://doi.org/10.1016/j.ccell.2016.05.003