A model system for studying the DNMT3A HOTSPO mutation (DNMT3AR882) demonstrates a causal relationship between its dominant-negative effect and leukemogenesis

Academic Article

Abstract

  • Mutation of DNA methyltransferase 3A at arginine 882 DNMT3A relied on a motif involved in heterodimer-(DNMT3A ) is prevalent in hematologic cancers and ization, whereas its various chromatin-binding domains were disorders. Recently, DNMT3A has been shown to have dispensable. Mutation of the heterodimerization motif that hypomorphic, dominant-negative, and/or gain-of-function interferes with DNMT3A binding to endogenous wild-effects on DNA methylation under different biological con-type DNMT proteins partially reversed the CpG hypomethyla-texts. However, the causal role for such a multifaceted effect of tion phenotype caused by DNMT3A , thus supporting a DNMT3A in leukemogenesis remains undetermined. dominant-negative mechanism in cells. In mice, bromodo-Here, we report TF-1 leukemia cells as a robust system useful main inhibition repressed gene-activation events downstream for modeling the DNMT3A -dependent transformation of DNMT3A -induced CpG hypomethylation, thereby and for dissecting the cause–effect relationship between mul-suppressing leukemogenesis mediated by DNMT3A . tifaceted activities of DNMT3A and leukemic transfor-Collectively, this study reports a model system useful for mation. Ectopic expression of DNMT3A and not wild-studying DNMT3A , shows a requirement of the dom-type DNMT3A promoted TF-1 cell transformation character-inant-negative effect by DNMT3A for leukemogenesis, ized by cytokine-independent growth, and induces CpG hypo- and describes an attractive strategy for the treatment of leu-methylation predominantly at enhancers. This effect was dose kemias carrying DNMT3A . dependent, acted synergistically with the isocitrate dehydro-genase 1 (IDH1) mutation, and resembled what was seen in Significance: These findings highlight a model system human leukemia patients carrying DNMT3A . The to study the functional impact of a hotspot mutation of transformation- and hypomethylation-inducing capacities of DNMT3A at R882 in leukemia. R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut R882mut
  • Authors

    Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Lu R; Wang J; Ren Z; Yin J; Wang Y; Cai L; Wang GG
  • Start Page

  • 3583
  • End Page

  • 3594
  • Volume

  • 79
  • Issue

  • 14