DNMT3A R882 Mutants Interact With Polycomb Proteins to Block Haematopoietic Stem and Leukaemic Cell Differentiation

Nat Commun. 2016 Mar 24;7:10924. doi: 10.1038/ncomms10924.

Abstract

Despite the clinical impact of DNMT3A mutation on acute myeloid leukaemia, the molecular mechanisms regarding how this mutation causes leukaemogenesis in vivo are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant haematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are downregulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells, representing a DNA methylation-independent role of mutated DNMT3A. DNMT3A R882H also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, the DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), causing transcriptional silencing, revealing a DNA methylation-independent role of DNMT3A mutation. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. From our data, it is shown that DNMT3A mutants can block the differentiation of HSCs and leukaemic cells via PRC1. This interaction could be targetable in DNMT3A-mutated leukaemias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation / genetics
  • Down-Regulation / drug effects
  • Gene Silencing / drug effects
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Mice, Inbred C57BL
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Polycomb Repressive Complex 1 / metabolism
  • Polycomb-Group Proteins / metabolism*
  • Protein Binding / drug effects
  • Tretinoin / pharmacology

Substances

  • Mutant Proteins
  • Polycomb-Group Proteins
  • Tretinoin
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Polycomb Repressive Complex 1
  • RNF2 protein, human