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

• Published in: Nature communications Vol. 3; no. 1; pp. 688 - 12
• Main Authors: Li, Zejuan, Huang, Hao, Chen, Ping, He, Miao, Li, Yuanyuan, Arnovitz, Stephen, Jiang, Xi, He, Chunjiang, Hyjek, Elizabeth, Zhang, Jun, Zhang, Zhiyu, Elkahloun, Abdel, Cao, Donglin, Shen, Chen, Wunderlich, Mark, Wang, Yungui, Neilly, Mary Beth, Jin, Jie, Wei, Minjie, Lu, Jun, Valk, Peter J.M., Delwel, Ruud, Lowenberg, Bob, Le Beau, Michelle M., Vardiman, James, Mulloy, James C., Zeleznik-Le, Nancy J., Liu, Paul P., Zhang, Jiwang, Chen, Jianjun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2012; Nature Publishing Group
• Subjects: 631/208/2489/144/68; 631/337/384/331; 692/699/67/1990/283; Animals; Apoptosis; Base Sequence; Bone marrow; Bone marrow transplantation; Cell differentiation; Cell Transformation, Neoplastic; Cells, Cultured; Differentiation (biology); Ectopic expression; fas Receptor - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Hematopoiesis - genetics; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemogenesis; Male; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - metabolism; miRNA; multidisciplinary; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid-Lymphoid Leukemia Protein - biosynthesis; Myeloid-Lymphoid Leukemia Protein - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncogenes; Phenotypes; Ribonucleic acid; RNA; Science; Sequence Analysis, DNA; Suppressors; Transplantation; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms1681

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. HOX9A and MEIS1 are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.