Author/Authors :
Bernt، نويسنده , , Kathrin M. and Zhu، نويسنده , , Nan and Sinha، نويسنده , , Amit U. and Vempati، نويسنده , , Sridhar and Faber، نويسنده , , Joerg and Krivtsov، نويسنده , , Andrei V. and Feng، نويسنده , , Zhaohui and Punt، نويسنده , , Natalie and Daigle، نويسنده , , Amanda and Bullinger، نويسنده , , Lars and Pollock، نويسنده , , Roy M. and Richon، نويسنده , , Victoria M. and Kung، نويسنده , , Andrew L. and Armstrong، نويسنده , , Scott A.، نويسنده ,
Abstract :
Summary
stone 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.
