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

Cancer cell | Jul 12, 2011

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.

Pubmed ID: 21741597 RIS Download

Mesh terms: Animals | Apoptosis | Cell Cycle | Cell Differentiation | Cell Transformation, Neoplastic | Gene Rearrangement | Genetic Loci | Hematopoiesis | Histones | Homeodomain Proteins | Humans | Lysine | Methylation | Methyltransferases | Mice | Myeloid Progenitor Cells | Myeloid-Lymphoid Leukemia Protein | Neoplasm Proteins | Oncogene Proteins, Fusion | Protein Processing, Post-Translational

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Associated grants

  • Agency: NCI NIH HHS, Id: CA684841
  • Agency: NCI NIH HHS, Id: U01 CA105423
  • Agency: NCI NIH HHS, Id: CA140575
  • Agency: NCI NIH HHS, Id: U01 CA105423-09
  • Agency: NHLBI NIH HHS, Id: K08 HL102264
  • Agency: NCI NIH HHS, Id: R01 CA140575-04
  • Agency: NCI NIH HHS, Id: CA105423
  • Agency: NIGMS NIH HHS, Id: GM083054
  • Agency: NCI NIH HHS, Id: R01 CA140575
  • Agency: NCI NIH HHS, Id: 1RC2CA148222
  • Agency: NCI NIH HHS, Id: RC2 CA148222

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