Author/Authors :
Daigle، نويسنده , , Scott R. and Olhava، نويسنده , , Edward J. and Therkelsen، نويسنده , , Carly A. and Majer، نويسنده , , Christina R. and Sneeringer، نويسنده , , Christopher J. and Song، نويسنده , , Jeffrey N. Johnston، نويسنده , , L. Danielle and Scott، نويسنده , , Margaret Porter and Smith، نويسنده , , Jesse J. and Xiao، نويسنده , , Yonghong and Jin، نويسنده , , Lei and Kuntz، نويسنده , , Kevin W. and Chesworth، نويسنده , , Richard W. Moyer، نويسنده , , Mikel P. and Bernt، نويسنده , , Kathrin M. and Tseng، نويسنده , , Jen-Chieh and Kung، نويسنده , , Andrew L. and Armstrong، نويسنده , , Scott A. and Copeland، نويسنده , , Robert A. and Richon، نويسنده , , Victoria M. and Pollock، نويسنده , , Roy M.، نويسنده ,
Abstract :
Summary
ated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
