TY - JOUR
T1 - MiR-150 blocks MLL-AF9-associated leukemia through oncogene repression
AU - Bousquet, Marina
AU - Zhuang, Guoqing
AU - Meng, Cong
AU - Ying, Wei
AU - Cheruku, Patali S.
AU - Shie, Andrew T.
AU - Wang, Stephanie
AU - Ge, Guangtao
AU - Wong, Piu
AU - Wang, Gang
AU - Safe, Stephen
AU - Zhou, Beiyan
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-13-0002-T
DO - 10.1158/1541-7786.MCR-13-0002-T
M3 - Article
C2 - 23604034
AN - SCOPUS:84882736736
VL - 11
SP - 912
EP - 922
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 8
ER -