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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Cell Differentiation
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Cells, Cultured
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Chromatin Immunoprecipitation
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Female
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Flow Cytometry
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic*
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Gene Rearrangement
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase
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Histones / chemistry
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Histones / genetics
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Histones / metabolism*
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Homeodomain Proteins / metabolism
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Humans
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Immunophenotyping
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Integrases / metabolism
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / pathology
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Lysine / chemistry
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Lysine / genetics
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Lysine / metabolism
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Male
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Methylation*
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Methyltransferases / antagonists & inhibitors
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Methyltransferases / physiology
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Mice
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Mice, Transgenic
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Myeloid-Lymphoid Leukemia Protein / physiology*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / physiology*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Principal Component Analysis
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Protein Methyltransferases / genetics
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Protein Methyltransferases / metabolism
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RNA, Small Interfering / pharmacology
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Transcription, Genetic
Substances
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Biomarkers, Tumor
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Histones
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Homeodomain Proteins
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MLL-AF4 fusion protein, human
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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Myeloid-Lymphoid Leukemia Protein
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HoxA protein
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DOT1L protein, human
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Dot1l protein, mouse
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Histone Methyltransferases
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Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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Cre recombinase
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Integrases
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Lysine