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

页码：66 / 78

页数：13

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