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

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): 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
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.

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Yang et al. show that expression of FLT3-ITD in mouse Dnmt3a^−/− and Dnmt3a^+/− hematopoietic stem cells preferentially induces lymphoid and myeloid leukemia, respectively. They show that mouse and human leukemias with DNMT3A mutations have reduced DNA methylation predominantly at hematopoietic enhancer regions.


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