AF10 Regulates Progressive H3K79 Methylation and HOX Gene Expression in Diverse AML Subtypes

被引：141

作者：

Deshpande, Aniruddha J. ^{[1
,6
,7
]}

Deshpande, Anagha ^{[6
,7
]}

Sinha, Amit U. ^{[6
,7
]}

Chen, Liying ^{[1
]}

Chang, Jenny ^{[6
,7
]}

Cihan, Ali ^{[5
]}

Fazio, Maurizio ^{[6
,7
]}

Chen, Chun-wei ^{[6
,7
]}

Zhu, Nan ^{[6
,7
]}

Koche, Richard ^{[6
,7
]}

Dzhekieva, Liuda ^{[2
]}

Ibanez, Gloria

Dias, Stuart ^{[1
]}

Banka, Deepti ^{[1
]}

Krivtsov, Andrei ^{[6
,7
]}

Luo, Minkui ^{[2
]}

Roeder, Robert G. ^{[5
]}

Bradner, James E. ^{[3
]}

Bernt, Kathrin M. ^{[4
]}

Armstrong, Scott A. ^{[1
,6
,7
]}

机构：

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

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[3] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Univ Colorado, Dept Pediat, Aurora, CO 80045 USA

[5] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

来源：

CANCER CELL | 2014年 / 26卷 / 06期

关键词：

ACUTE MYELOID-LEUKEMIA; METHYLTRANSFERASE ACTIVITY; CHROMATIN MODIFICATIONS; STEM-CELLS; ADULT AML; DOT1L; EZH2; FUSION; INHIBITION; PROTEIN;

D O I：

10.1016/j.ccell.2014.10.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Homeotic (HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at HOX loci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1-to-H3K79me2 conversion is regulated by the DOT1L cofactor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6, and NUP98-NSD1 fusions-mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1-transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/JAF10 complex may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.

引用

页码：896 / 908

页数：13

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