ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression

被引：472

作者：

Abdel-Wahab, Omar ^{[3
,4
]}

Adli, Mazhar ^{[1
,2
]}

LaFave, Lindsay M. ^{[3
,4
,5
]}

Gao, Jie ^{[7
,8
]}

Hricik, Todd ^{[3
,4
]}

Shih, Alan H. ^{[3
,4
]}

Pandey, Suveg ^{[3
,4
]}

Patel, Jay P. ^{[3
,4
]}

Chung, Young Rock ^{[3
,4
]}

Koche, Richard ^{[1
,2
]}

Perna, Fabiana ^{[6
]}

Zhao, Xinyang ^{[9
]}

Taylor, Jordan E. ^{[10
]}

Park, Christopher Y. ^{[3
,4
]}

Carroll, Martin ^{[11
]}

Melnick, Ari ^{[12
]}

Nimer, Stephen D. ^{[14
]}

Jaffe, Jacob D. ^{[10
]}

Aifantis, Iannis ^{[6
]}

Bernstein, Bradley E. ^{[1
,2
]}

Levine, Ross L. ^{[3
,4
,13
]}

机构：

[1] Massachusetts Gen Hosp, Howard Hughes Med Inst, Broad Inst Harvard & MIT, Dept Pathol, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Boston, MA 02114 USA

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

[4] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Sch Biomed Sci, New York, NY 10065 USA

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

[7] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA

[8] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[9] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL 35233 USA

[10] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[11] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA

[12] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY 10065 USA

[13] Weill Cornell Med Coll, Biochem & Mol Biol Program, New York, NY 10065 USA

[14] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

来源：

CANCER CELL | 2012年 / 22卷 / 02期

关键词：

CHRONIC MYELOMONOCYTIC LEUKEMIA; EMBRYONIC STEM-CELLS; MYELODYSPLASTIC SYNDROMES; SOMATIC MUTATIONS; HEMATOPOIETIC-CELLS; SELF-RENEWAL; COMPLEX; EZH2; CHROMATIN; DIFFERENTIATION;

D O I：

10.1016/j.ccr.2012.06.032

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.

引用

页码：180 / 193

页数：14

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