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

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

Authors

  • Bernt KM
  • Zhu N
  • Sinha AU
  • Vempati S
  • Faber J
  • Krivtsov AV
  • Feng Z
  • Punt N
  • Daigle A
  • Bullinger L
  • Pollock RM
  • Richon VM
  • Kung AL
  • Armstrong SA

Journal

Cancer cell

Publication Data

July 12, 2011

Associated Grants

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

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