MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia

被引：305

作者：

Chen, Chong ^{[1
]}

Liu, Yu ^{[1
]}

Rappaport, Amy R. ^{[2
]}

Kitzing, Thomas ^{[1
]}

Schultz, Nikolaus ^{[3
]}

Zhao, Zhen ^{[1
]}

Shroff, Aditya S. ^{[1
]}

Dickins, Ross A. ^{[4
]}

Vakoc, Christopher R. ^{[2
]}

Bradner, James E. ^{[5
]}

Stock, Wendy ^{[6
]}

LeBeau, Michelle M. ^{[6
]}

Shannon, Kevin M. ^{[7
]}

Kogan, Scott ^{[8
,9
]}

Zuber, Johannes ^{[2
,10
]}

Lowe, Scott W. ^{[1
,11
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[3] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA

[4] Walter & Eliza Hall Inst Med Res, Div Mol Med, Parkville, Vic 3052, Australia

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[6] Univ Chicago, Sect Hematol Oncol, Chicago, IL 60637 USA

[7] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94158 USA

[9] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[10] Res Inst Mol Pathol, A-1030 Vienna, Austria

[11] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

CANCER CELL | 2014年 / 25卷 / 05期

关键词：

HEMATOPOIETIC-CELLS; GENOME; GENE; CHROMATIN; INACTIVATION; MUTATIONS; PATHWAYS; MOUSE; P53; RECRUITMENT;

D O I：

10.1016/j.ccr.2014.03.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an -50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.

引用

页码：652 / 665

页数：14

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