hDOT1L Links Histone Methylation to Leukemogenesis
Copyright policy )hDOT1L Links Histone Methylation to Leukemogenesis
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 , concomitant with hypermethylation of H3-K79. Our studies thus establish that mistargeting of hDOT1L to 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.
- Chinese Academy of Sciences China (People's Republic of)
- Center for Excellence in Molecular Cell Science China (People's Republic of)
- MRC Laboratory of Molecular Biology United Kingdom
- UNC Lineberger Comprehensive Cancer Center United States
- University of North Carolina at Chapel Hill United States
Homeodomain Proteins, Leukemia, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Regulation, Leukemic, Recombinant Fusion Proteins, Histone-Lysine N-Methyltransferase, Methyltransferases, Saccharomyces cerevisiae, Methylation, Epigenesis, Genetic, Neoplasm Proteins, DNA-Binding Proteins, Histones, Mice, Cell Transformation, Neoplastic, Proto-Oncogenes, Animals, Humans, RNA, Small Interfering, Myeloid-Lymphoid Leukemia Protein, Cell Line, Transformed
Homeodomain Proteins, Leukemia, Biochemistry, Genetics and Molecular Biology(all), Gene Expression Regulation, Leukemic, Recombinant Fusion Proteins, Histone-Lysine N-Methyltransferase, Methyltransferases, Saccharomyces cerevisiae, Methylation, Epigenesis, Genetic, Neoplasm Proteins, DNA-Binding Proteins, Histones, Mice, Cell Transformation, Neoplastic, Proto-Oncogenes, Animals, Humans, RNA, Small Interfering, Myeloid-Lymphoid Leukemia Protein, Cell Line, Transformed
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