Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development

Cancer Cell. 2016 Jul 11;30(1):92-107. doi: 10.1016/j.ccell.2016.05.008. Epub 2016 Jun 23.

Abstract

DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that the DNMT3A mutational hotspot at Arg882 (DNMT3A(R882H)) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A(R882H) directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1, and Hoxa gene cluster. DNMT3A(R882H) induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A(R882H)-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A(R882H)-induced gene-expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias.

Publication types

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

MeSH terms

  • Animals
  • Arginine / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Genes, ras
  • Homeodomain Proteins / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Methyltransferases / antagonists & inhibitors
  • Mice
  • Mutation
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins / genetics
  • Neoplasms, Experimental
  • Promoter Regions, Genetic
  • Stem Cells / cytology
  • Stem Cells / pathology*
  • Tumor Cells, Cultured

Substances

  • Homeodomain Proteins
  • MEIS1 protein, human
  • Meis1 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Arginine
  • Methyltransferases
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A