MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L

Cancer Cell. 2011 Jul 12;20(1):66-78. doi: 10.1016/j.ccr.2011.06.010.

Abstract

The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Differentiation
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Gene Rearrangement / genetics*
  • Genetic Loci / genetics
  • Hematopoiesis
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Lysine / metabolism*
  • Methylation
  • Methyltransferases / metabolism*
  • Mice
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Myeloid Progenitor Cells / metabolism
  • Myeloid Progenitor Cells / pathology
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplasm Proteins / metabolism
  • Oncogene Proteins, Fusion / metabolism
  • Protein Processing, Post-Translational

Substances

  • Histones
  • Homeodomain Proteins
  • MLL-AF9 fusion protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Lysine

Associated data

  • GEO/GSE25911
  • GEO/GSE29130