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H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

We created a mouse model wherein conditional expression of an Mll-AF4 fusion oncogene induces B precursor acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Gene expression profile analysis of the ALL cells demonstrated significant overlap with human MLL-rearranged ALL. ChIP-chip analysis demonstrated histone H3 lysine 79 (H3K79) methylation profiles that correlated with Mll-AF4-associated gene expression profiles in murine ALLs and in human MLL-rearranged leukemias. Human MLL-rearranged ALLs could be distinguished from other ALLs by their H3K79 profiles, and suppression of the H3K79 methyltransferase DOT1L inhibited expression of critical MLL-AF4 target genes. We thus demonstrate that ectopic H3K79 methylation is a distinguishing feature of murine and human MLL-AF4 ALLs and is important for maintenance of MLL-AF4-driven gene expression.

Pubmed ID: 18977325


  • Krivtsov AV
  • Feng Z
  • Lemieux ME
  • Faber J
  • Vempati S
  • Sinha AU
  • Xia X
  • Jesneck J
  • Bracken AP
  • Silverman LB
  • Kutok JL
  • Kung AL
  • Armstrong SA


Cancer cell

Publication Data

November 4, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: 5P01CA0684841
  • Agency: NCI NIH HHS, Id: 5U01CA105423
  • Agency: NCI NIH HHS, Id: K08 CA092551
  • Agency: NCI NIH HHS, Id: K08 CA092551-05
  • Agency: NCI NIH HHS, Id: K08CA92551
  • Agency: NCI NIH HHS, Id: P01 CA068484
  • Agency: NCI NIH HHS, Id: P01 CA068484-130015
  • Agency: NCI NIH HHS, Id: U01 CA105423
  • Agency: NCI NIH HHS, Id: U01 CA105423-05

Mesh Terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Homeodomain Proteins
  • Humans
  • Immunophenotyping
  • Integrases
  • Leukemia, Myeloid, Acute
  • Lysine
  • Male
  • Methylation
  • Methyltransferases
  • Mice
  • Mice, Transgenic
  • Myeloid-Lymphoid Leukemia Protein
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins, Fusion
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Principal Component Analysis
  • Protein Methyltransferases
  • RNA, Small Interfering
  • Transcription, Genetic
  • Tumor Markers, Biological