TY - JOUR
T1 - MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
AU - Li, Zejuan
AU - Huang, Hao
AU - Chen, Ping
AU - He, Miao
AU - Li, Yuanyuan
AU - Arnovitz, Stephen
AU - Jiang, Xi
AU - He, Chunjiang
AU - Hyjek, Elizabeth
AU - Zhang, Jun
AU - Zhang, Zhiyu
AU - Elkahloun, Abdel
AU - Cao, Donglin
AU - Shen, Chen
AU - Wunderlich, Mark
AU - Wang, Yungui
AU - Neilly, Mary Beth
AU - Jin, Jie
AU - Wei, Minjie
AU - Lu, Jun
AU - Valk, Peter J.M.
AU - Delwel, Ruud
AU - Lowenberg, Bob
AU - Le Beau, Michelle M.
AU - Vardiman, James
AU - Mulloy, James C.
AU - Zeleznik-Le, Nancy J.
AU - Liu, Paul P.
AU - Zhang, Jiwang
AU - Chen, Jianjun
N1 - Funding Information:
We thank Dr. Janet D. Rowley and Colles Price for their constructive suggestions and comments, and Drs Gang Huang, Long Zhang and Roger Luo for their technical support on isolation and retroviral transduction of mouse foetal liver cells, mouse tail vein injection and general mouse BM transplantation assays. We are also grateful to Drs Gregory Hannon, Scott Hammond, Lin He, Scott Armstrong and Michael Thirman for providing retroviral constructs. This work was supported in part by the National Institutes of Health (NIH) R01 grant CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), LLS Special Fellowship (Z.L.), Gabrielle’s Angel Fondation for Cancer Research (J.C.; Z.L.; H.H.), Leukemia and Lymphoma Society (LLS) Translational Research Grant (J.C.), Fidelity Foundation (J.C.), NIH R01 CA118319 Sub-Award (J.C.M. and J.C.), R01 HL95896 (J.Z.), HL087188 (N.J.Z.-L.), Intramural Research Program of National Human Genome Research Institute, NIH (A.E. and P.P.L.), NIH P01 CA40046 (M.M.L.B) and P30 CA014599 (CCSG) (M.M.L.B). J.C.M. is a Leukemia and Lymphoma Society (LLS) Scholar.
PY - 2012
Y1 - 2012
N2 - HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.
AB - HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.
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U2 - 10.1038/ncomms1681
DO - 10.1038/ncomms1681
M3 - Article
C2 - 22353710
AN - SCOPUS:84863283403
SN - 2041-1723
VL - 3
JO - Nature Communications
JF - Nature Communications
M1 - 688
ER -