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; Jianjun Chen

doi:10.1038/ncomms11452

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. LarsonMichelle M. Le Beau, Tobias Herold, Stefan K. Bohlander, Paul P. Liu, Jiwang Zhang, Zejuan Li, Chuan He, Jie Jin, Seungpyo Hong, Jianjun Chen

Houston Methodist

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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/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.

Original language	English (US)
Article number	11452
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11452
State	Published - Apr 26 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms11452

Cite this

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., ... Chen, J. (2016). MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. Nature Communications, 7, Article 11452. https://doi.org/10.1038/ncomms11452

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, AG, Yang, Y, Neilly, MB, Larson, RA, Le Beau, MM, Herold, T, Bohlander, SK, Liu, PP, Zhang, J, Li, Z, He, C, Jin, J, Hong, S & Chen, J 2016, 'MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia', Nature Communications, vol. 7, 11452. https://doi.org/10.1038/ncomms11452

@article{4cdfb963280244d49f850cbaebd22b55,

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/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.",

author = "Xi Jiang and Chao Hu and Stephen Arnovitz and Jason Bugno and Miao Yu and Zhixiang Zuo and Ping Chen and Hao Huang and Bryan Ulrich and Sandeep Gurbuxani and Hengyou Weng and Jennifer Strong and Yungui Wang and Yuanyuan Li and Justin Salat and Shenglai Li and Elkahloun, {Abdel G.} and Yang Yang and Neilly, {Mary Beth} and Larson, {Richard A.} and {Le Beau}, {Michelle M.} and Tobias Herold and Bohlander, {Stefan K.} and Liu, {Paul P.} and Jiwang Zhang and Zejuan Li and Chuan He and Jie Jin and Seungpyo Hong and Jianjun Chen",

note = "Funding 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.",

year = "2016",

month = apr,

day = "26",

doi = "10.1038/ncomms11452",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

AU - Jiang, Xi

AU - Hu, Chao

AU - Arnovitz, Stephen

AU - Bugno, Jason

AU - Yu, Miao

AU - Zuo, Zhixiang

AU - Chen, Ping

AU - Huang, Hao

AU - Ulrich, Bryan

AU - Gurbuxani, Sandeep

AU - Weng, Hengyou

AU - Strong, Jennifer

AU - Wang, Yungui

AU - Li, Yuanyuan

AU - Salat, Justin

AU - Li, Shenglai

AU - Elkahloun, Abdel G.

AU - Yang, Yang

AU - Neilly, Mary Beth

AU - Larson, Richard A.

AU - Le Beau, Michelle M.

AU - Herold, Tobias

AU - Bohlander, Stefan K.

AU - Liu, Paul P.

AU - Zhang, Jiwang

AU - Li, Zejuan

AU - He, Chuan

AU - Jin, Jie

AU - Hong, Seungpyo

AU - Chen, Jianjun

N1 - Funding 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.

PY - 2016/4/26

Y1 - 2016/4/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84964686288&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964686288&partnerID=8YFLogxK

U2 - 10.1038/ncomms11452

DO - 10.1038/ncomms11452

M3 - Article

C2 - 27116251

AN - SCOPUS:84964686288

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11452

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this