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Nat Commun. 2016 Apr 26;7:11452. doi: 10.1038/ncomms11452.

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

Author information

1
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.
2
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
3
Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China.
4
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA.
5
Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.
6
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China.
7
Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
8
Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
9
Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
10
Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, New Zealand.
11
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153, USA.
12
Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
13
Integrated Science and Engineering Division, Underwood International College, Yonsei University, Incheon 406-840, Korea.

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.

PMID:
27116251
PMCID:
PMC5477496
DOI:
10.1038/ncomms11452
[Indexed for MEDLINE]
Free PMC Article

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