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

Cancer Cell. 2016 Jun 13;29(6):922-934. doi: 10.1016/j.ccell.2016.05.003.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation*
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Humans
  • Leukemia / genetics*
  • Mice
  • Mutation
  • Neoplasms, Experimental
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3