MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
Copyright policy )MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
- Dana-Farber Cancer Institute United States
- University of Ulm Germany
- Harvard University United States
- Harvard Stem Cell Institute, Cambridge, MA, USA United States
- Johannes Gutenberg University of Mainz Germany
Cancer Research, Apoptosis, Methylation, Histones, Mice, Animals, Humans, Myeloid Ecotropic Viral Integration Site 1 Protein, Myeloid Progenitor Cells, Gene Rearrangement, Homeodomain Proteins, Lysine, Cell Cycle, Cell Differentiation, Cell Biology, Histone-Lysine N-Methyltransferase, Methyltransferases, Hematopoiesis, Neoplasm Proteins, Cell Transformation, Neoplastic, Oncology, Genetic Loci, Myeloid-Lymphoid Leukemia Protein
Cancer Research, Apoptosis, Methylation, Histones, Mice, Animals, Humans, Myeloid Ecotropic Viral Integration Site 1 Protein, Myeloid Progenitor Cells, Gene Rearrangement, Homeodomain Proteins, Lysine, Cell Cycle, Cell Differentiation, Cell Biology, Histone-Lysine N-Methyltransferase, Methyltransferases, Hematopoiesis, Neoplasm Proteins, Cell Transformation, Neoplastic, Oncology, Genetic Loci, Myeloid-Lymphoid Leukemia Protein
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