miR-150 Blocks MLL-AF9-Associated Leukemia through Oncogene Repression

被引:29
作者
Bousquet, Marina [1 ,5 ]
Zhuang, Guoqing
Meng, Cong
Ying, Wei [4 ]
Cheruku, Patali S.
Shie, Andrew T. [1 ,2 ]
Wang, Stephanie [1 ,2 ]
Ge, Guangtao [3 ]
Wong, Piu [1 ]
Wang, Gang
Safe, Stephen
Zhou, Beiyan
机构
[1] Whitehead Inst Biomed Res, Cambridge, England
[2] MIT, Dept Biol, Cambridge, MA USA
[3] LeapFrogRx Inc, Waltham, MA USA
[4] Texas A&M Univ, Dept Anim Sci, College Stn, TX 77843 USA
[5] CHU Purpan, CRCT, INSERM, U1037, Toulouse, France
关键词
ACUTE MYELOID-LEUKEMIA; MICRORNA EXPRESSION PROFILES; ACUTE LYMPHOBLASTIC-LEUKEMIA; C-MYB; STEM-CELLS; IMMUNE-SYSTEM; MLL; TARGET; DIFFERENTIATION; PROGENITORS;
D O I
10.1158/1541-7786.MCR-13-0002-T
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in mixed-lineage leukemia (MLL). In this study, miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using MLL-AF9-transformed cells, we demonstrate that ectopic expression of miR-150 inhibits blast colony formation, cell growth, and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in MLL-AF9-transformed cells completely blocked the development of myeloid leukemia in transplanted mice. Furthermore, gene expression profiling revealed that miR-150 altered the expression levels of more than 30 "stem cell signature" genes and many others that are involved in critical cancer pathways. In addition to the known miR-150 target Myb, we also identified Cbl and Egr2 as bona fide targets and shRNA-mediated suppression of these genes recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression. In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes. Implications: These data establish new, key players for the development of therapeutic strategies to treat MLL-AF9-related leukemia. (C) 2013 AACR.
引用
收藏
页码:912 / 922
页数:11
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