Abstract
Epigenetic modifications play an important role in human cancer. One such modification, histone methylation, contributes to human cancer through deregulation of cancer-relevant genes. The yeast Dot1 and its human counterpart, hDOT1L, methylate lysine 79 located within the globular domain of histone H3. Here we report that hDOT1L interacts with AF10, an MLL (mixed lineage leukemia) fusion partner involved in acute myeloid leukemia, through the OM-LZ region of AF10 required for MLL-AF10-mediated leukemogenesis. We demonstrate that direct fusion of hDOT1L to MLL results in leukemic transformation in an hDOT1L methyltransferase activity-dependent manner. Transformation by MLL-hDOT1L and MLL-AF10 results in upregulation of a number of leukemia-relevant genes, such as Hoxa9, concomitant with hypermethylation of H3-K79. Our studies thus establish that mistargeting of hDOT1L to Hoxa9 plays an important role in MLL-AF10-mediated leukemogenesis and suggests that the enzymatic activity of hDOT1L may provide a potential target for therapeutic intervention.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line, Transformed
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Cell Transformation, Neoplastic
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epigenesis, Genetic / physiology
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Gene Expression Regulation, Leukemic
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Histone-Lysine N-Methyltransferase
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Histones / metabolism*
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Homeodomain Proteins / genetics
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Humans
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Leukemia / genetics*
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Leukemia / metabolism*
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Methylation
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Methyltransferases / genetics*
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Methyltransferases / metabolism*
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Mice
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Myeloid-Lymphoid Leukemia Protein
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Neoplasm Proteins / genetics
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Proto-Oncogenes / genetics
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RNA, Small Interfering
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae
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Stem Cells / cytology
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Stem Cells / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation
Substances
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DNA-Binding Proteins
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HOXA7 protein, human
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Histones
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Homeodomain Proteins
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KMT2A protein, human
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MLLT10 protein, human
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Neoplasm Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Transcription Factors
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homeobox protein HOXA9
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Myeloid-Lymphoid Leukemia Protein
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DOT1L protein, human
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Methyltransferases
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Histone-Lysine N-Methyltransferase
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Kmt2a protein, mouse