Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor

被引：751

作者：

Daigle, Scott R. ^{[1
]}

Olhava, Edward J. ^{[1
]}

Therkelsen, Carly A. ^{[1
]}

Majer, Christina R. ^{[1
]}

Sneeringer, Christopher J. ^{[1
]}

Song, Jeffrey ^{[1
]}

Johnston, L. Danielle ^{[1
]}

Scott, Margaret Porter ^{[1
]}

Smith, Jesse J. ^{[1
]}

Xiao, Yonghong ^{[2
]}

Jin, Lei ^{[1
]}

Kuntz, Kevin W. ^{[1
]}

Chesworth, Richard ^{[1
]}

Moyer, Mike P. ^{[1
]}

Bernt, Kathrin M. ^{[3
,4
,5
]}

Tseng, Jen-Chieh ^{[6
]}

Kung, Andrew L. ^{[3
,4
,5
,6
]}

Armstrong, Scott A. ^{[3
,4
,5
,7
]}

Copeland, Robert A. ^{[1
]}

Richon, Victoria M. ^{[1
]}

Pollock, Roy M. ^{[1
]}

机构：

[1] Epizyme Inc, Cambridge, MA 02139 USA

[2] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

[3] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Med, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA

[7] Harvard Stem Cell Inst, Boston, MA 02138 USA

来源：

CANCER CELL | 2011年 / 20卷 / 01期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; HISTONE METHYLTRANSFERASE; MLL TRANSLOCATIONS; H3K79; METHYLATION; SET DOMAIN; GENE; MEIS1; HOXA9; CLASSIFICATION; TRANSCRIPTION;

D O I：

10.1016/j.ccr.2011.06.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mislocated 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.

引用

页码：53 / 65

页数：13

共 45 条

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