MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L

被引：717
作者：
Bernt, Kathrin M. [1 ,2 ]
Zhu, Nan [1 ,2 ]
Sinha, Amit U. [1 ,2 ]
Vempati, Sridhar [1 ,2 ]
Faber, Joerg [3 ]
Krivtsov, Andrei V. [1 ,2 ]
Feng, Zhaohui [1 ,2 ]
Punt, Natalie [1 ,2 ]
Daigle, Amanda [1 ,2 ]
Bullinger, Lars [4 ]
Pollock, Roy M. [5 ]
Richon, Victoria M. [5 ]
Kung, Andrew L. [1 ,2 ,6 ]
Armstrong, Scott A. [1 ,2 ,6 ]
机构：
[1] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA
[3] Johannes Gutenberg Univ Mainz, D-05131 Mainz, Germany
[4] Univ Ulm, D-98091 Ulm, Germany
[5] Epizyme Inc, Cambridge, MA 02139 USA
[6] Harvard Stem Cell Inst, Boston, MA 02138 USA
来源：
CANCER CELL | 2011年 / 20卷 / 01期
关键词：
METHYLTRANSFERASE GENE EZH2; MIXED-LINEAGE LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HISTONE METHYLTRANSFERASE; MYELODYSPLASTIC SYNDROMES; SOMATIC MUTATIONS; TRANSCRIPTION; LEUKEMOGENESIS; EXPRESSION; CHROMATIN;
D O I：
10.1016/j.ccr.2011.06.010
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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.
引用
收藏
页码：66 / 78
页数：13
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