miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

• Published in: Nature communications Vol. 7; no. 1; p. 11452
• Main Authors: Jiang, Xi, Hu, Chao, Arnovitz, Stephen, Bugno, Jason, Yu, Miao, Zuo, Zhixiang, Chen, Ping, Huang, Hao, Ulrich, Bryan, Gurbuxani, Sandeep, Weng, Hengyou, Strong, Jennifer, Wang, Yungui, Li, Yuanyuan, Salat, Justin, Li, Shenglai, Elkahloun, Abdel G., Yang, Yang, Neilly, Mary Beth, Larson, Richard A., Le Beau, Michelle M., Herold, Tobias, Bohlander, Stefan K., Liu, Paul P., Zhang, Jiwang, Li, Zejuan, He, Chuan, Jin, Jie, Hong, Seungpyo, Chen, Jianjun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.04.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 631/337/384/331; 631/67/1059; 631/67/1990/283/1897; 631/80/86; 64; 96; Acute Disease; Animals; Breast cancer; Cell Line; Cell Line, Tumor; Cell Proliferation - genetics; Down-Regulation; Epigenesis, Genetic; Epigenetics; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genes, Tumor Suppressor; HEK293 Cells; Hematology; Humanities and Social Sciences; Humans; Leukemia; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Medicine; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - therapeutic use; multidisciplinary; Mutation; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Oncology; Pathogenesis; Roles; Science; Science (multidisciplinary); Signal Transduction - genetics; Chicago Illinois; United States > US; Illinois; China
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11452

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro , and substantially inhibits leukaemia development and maintenance in vivo . Mechanistically, miR-22 targets multiple oncogenes, including CRTC1 , FLT3 and MYCBP , and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo . Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. Mir-22 has been shown to be an oncogenic microRNA in breast cancer and myelodysplastic syndrome. Here, the authors show that mir-22 functions as a tumour suppressor in de novo acute myeloid leukaemia by inhibiting the expression of several oncogenes and that restoring mir-22 expression suppresses AML progression.