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/SIN3Amediated 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.
Bibliographical noteFunding Information:
Special thanks to the late Dr Janet Rowley for her long-term support. We also thank Drs Pier P. Pandolfi, Sheena Josselyn, Dong-Er Zhang, Scott Armstrong, Michael Cleary, James Mulloy, Robert Slany, Lin He and Michael Thirman for providing mouse models, retroviral constructs or cell lines, and the German AMLCG study group for AML microarray data. This work was supported by Leukemia and Lymphoma Society (LLS) Translational Research Grant (J.C.), the National Institutes of Health (NIH) R01 Grants A178454, CA182528 and CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), The University of Chicago Committee on Cancer Biology (CCB) Fellowship Program (X.J.), LLS Special Fellowship (Z.L.), Gabrielle's Angel Foundation or Cancer Research (J.C., Z.L., X.J. and H.H.) and Intramural Research Program of National Human Genome Research Institute, NIH (A.G.E. and P.P.L.). C.H. is an investigator of the Howard Hughes Medical Institute.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)