H3K79 methylation profiles define murine and human MLL-AF4 leukemias

Cancer Cell. 2008 Nov 4;14(5):355-68. doi: 10.1016/j.ccr.2008.10.001.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

  • Biomarkers, Tumor
  • Histones
  • Homeodomain Proteins
  • MLL-AF4 fusion protein, human
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • Myeloid-Lymphoid Leukemia Protein
  • HoxA protein
  • DOT1L protein, human
  • Dot1l protein, mouse
  • Histone Methyltransferases
  • Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Cre recombinase
  • Integrases
  • Lysine

Associated data

  • GEO/GSE12363