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

Authors: Jiang, X; Hu, C; Arnovitz, S; Bugno, J.; Yu, M; Zuo, Z.; Chen, P; Huang, H; Ulrich, B.; Gurbuxani, S.; Weng, H.; Strong, J.; Wang, Y; Li, Y; Salat, J.; Li, S; Elkahloun, A. G.; Yang, Y; Neilly, M. B.; Larson, R. A.; Le Beau, M. M.; Herold, T.; Bohlander, S. K.; Liu, P. P.; Zhang, J; Li, Z; He, C; Jin, J; Hong, S.; Chen, J
Article Title: miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia
Abstract: 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.
Journal Title: Nature communications
Volume: 7
ISSN: 2041-1723; 2041-1723
Publisher: Unknown  
Journal Place: England
Date Published: 2016
Start Page: 11452
Language: eng
Notes: JID: 101528555; 2016/01/08 [received]; 2016/03/23 [accepted]; epublish