miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.
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.
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Xi
X
Jiang
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.|Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China.
Chao
C
Hu
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Stephen
S
Arnovitz
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA.
Jason
J
Bugno
Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.
Miao
M
Yu
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China.
Zhixiang
Z
Zuo
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Ping
P
Chen
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Hao
H
Huang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Bryan
B
Ulrich
Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
Sandeep
S
Gurbuxani
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Hengyou
H
Weng
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.
Jennifer
J
Strong
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.|Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China.
Yungui
Y
Wang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Yuanyuan
Y
Li
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Justin
J
Salat
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Shenglai
S
Li
Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
Abdel G
AG
Elkahloun
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA.
Yang
Y
Yang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Mary Beth
MB
Neilly
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Richard A
RA
Larson
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Michelle M
MM
Le Beau
Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
Tobias
T
Herold
Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, New Zealand.
Stefan K
SK
Bohlander
Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
Paul P
PP
Liu
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Jiwang
J
Zhang
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.|Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Zejuan
Z
Li
Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.
Chuan
C
He
Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China.
Jie
J
Jin
Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA.|Integrated Science and Engineering Division, Underwood International College, Yonsei University, Incheon 406-840, Korea.
Seungpyo
S
Hong
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.|Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Jianjun
J
Chen
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000627:therapeutic use; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
C548375:MIRN22 microRNA, human; D035683:MicroRNAs