MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
Cancer Cell, 2011/7/12;20(1):66-78.
Bernt KM[1], Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, Pollock RM, Richon VM, Kung AL, Armstrong SA
Affiliations
PMID: 21741597DOI: 10.1016/j.ccr.2011.06.010
Impact factor: 38.585
Abstract
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.
MeSH terms
Animals; Apoptosis; Cell Cycle; Cell Differentiation; Cell Transformation, Neoplastic; Gene Rearrangement; Genetic Loci; Hematopoiesis; Histone-Lysine N-Methyltransferase; Histones; Homeodomain Proteins; Humans; Lysine; Methylation; Methyltransferases; Mice; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid Progenitor Cells; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Oncogene Proteins, Fusion; Protein Processing, Post-Translational
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