کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2107408 | 1083674 | 2011 | 13 صفحه PDF | دانلود رایگان |
SummaryThe 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.
► MLL-AF9 promotes enhanced H3K79me2 at fusion target genes
► H3K79me2 is specifically abnormal as compared to other histone modifications
► Loss of Dot1l selectively decreases leukemia-associated gene expression
► Dot1l is absolutely required for MLL-rearranged leukemia cell growth in vitro and in vivo
Journal: - Volume 20, Issue 1, 12 July 2011, Pages 66–78