miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia Journal Article

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Authors: Li, Z; Huang, H; Chen, P; He, M; Li, Y; Arnovitz, S; Jiang, X; He, C; Hyjek, E; Zhang, J; Zhang, Z; Elkahloun, A; Cao, D; Shen, C; Wunderlich, M; Wang, Y; Neilly, M. B.; Jin, J; Wei, M; Lu, J; Valk, P. J.; Delwel, R; Lowenberg, B; Le Beau, M. M.; Vardiman, J; Mulloy, J. C.; Zeleznik-Le, N. J.; Liu, P. P.; Chen, J
Article Title: miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
Abstract: 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.
Journal Title: Nature communications
Volume: 3
ISSN: 2041-1723; 2041-1723
Publisher: Unknown  
Journal Place: England
Date Published: 2012
Start Page: 688
Language: eng
DOI/URL:

10.1038/ncomms1681

10.1038/ncomms1681
Notes: LR: 20130626; GR: CA127277/CA/NCI NIH HHS/United States; GR: HL087188/HL/NHLBI NIH HHS/United States; GR: P01 CA40046/CA/NCI NIH HHS/United States; GR: P30 CA014599/CA/NCI NIH HHS/United States; GR: R01 CA118319/CA/NCI NIH HHS/United States; GR: R01 HL087188/HL/NHLBI NIH HHS/United States; GR: R01 HL95896/HL/NHLBI NIH HHS/United States; GR: ZIC HG200365-01/HG/NHGRI NIH HHS/United States; GR: ZIC HG200365-02/HG/NHGRI NIH HHS/United States; GR: ZIC HG200365-03/HG/NHGRI NIH HHS/United States; JID: 101528555; 0 (Antigens, CD95); 0 (FAS protein, human); 0 (Homeodomain Proteins); 0 (MIRN196 microRNA, human); 0 (MicroRNAs); 0 (Neoplasm Proteins); 0 (homeobox protein HOXA9); 0 (myeloid ecotropic viral integration site 1 protein); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); NIHMS420235; OID: NLM: NIHMS420235; OID: NLM: PMC3514459; 2011/11/03 [received]; 2012/01/11 [accepted]; epublish