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

Xi Jiang, Chao Hu, Stephen Arnovitz, Jason Bugno, Miao Yu, Zhixiang Zuo, Ping Chen, Hao Huang, Bryan Ulrich, Sandeep Gurbuxani, Hengyou Weng, Jennifer Strong, Yungui Wang, Yuanyuan Li, Justin Salat, Shenglai Li, Abdel G. Elkahloun, Yang Yang, Mary Beth Neilly, Richard A. Larson, Michelle M. Le Beau, Tobias Herold, Stefan K. Bohlander, Paul P. Liu, Jiwang Zhang, Zejuan Li, Chuan He, Jie Jin, Seungpyo Hong and Jianjun Chen ()
Additional contact information
Xi Jiang: University of Cincinnati
Chao Hu: University of Cincinnati
Stephen Arnovitz: Section of Hematology/Oncology, University of Chicago
Jason Bugno: The University of Illinois
Miao Yu: Howard Hughes Medical Institute, University of Chicago
Zhixiang Zuo: University of Cincinnati
Ping Chen: Section of Hematology/Oncology, University of Chicago
Hao Huang: Section of Hematology/Oncology, University of Chicago
Bryan Ulrich: Section of Hematology/Oncology, University of Chicago
Sandeep Gurbuxani: University of Chicago
Hengyou Weng: University of Cincinnati
Jennifer Strong: University of Cincinnati
Yungui Wang: University of Cincinnati
Yuanyuan Li: Section of Hematology/Oncology, University of Chicago
Justin Salat: Section of Hematology/Oncology, University of Chicago
Shenglai Li: Section of Hematology/Oncology, University of Chicago
Abdel G. Elkahloun: National Human Genome Research Institute, NIH
Yang Yang: The University of Illinois
Mary Beth Neilly: Section of Hematology/Oncology, University of Chicago
Richard A. Larson: Section of Hematology/Oncology, University of Chicago
Michelle M. Le Beau: Section of Hematology/Oncology, University of Chicago
Tobias Herold: University Hospital Grosshadern, Ludwig-Maximilians-Universität
Stefan K. Bohlander: University of Auckland
Paul P. Liu: National Human Genome Research Institute, NIH
Jiwang Zhang: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center
Zejuan Li: Section of Hematology/Oncology, University of Chicago
Chuan He: Howard Hughes Medical Institute, University of Chicago
Jie Jin: The First Affiliated Hospital Zhejiang University
Seungpyo Hong: The University of Illinois
Jianjun Chen: University of Cincinnati

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11452

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