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

Research output: Contribution to journalArticle

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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 languageEnglish
Article number11452
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 Apr 26

Fingerprint

leukemias
MicroRNAs
Acute Myeloid Leukemia
Tumors
tumors
Cells
Nanoparticles
Networks (circuits)
DNA
Epigenetic Repression
Neoplasms
Leukemia
Down-Regulation
Myelodysplastic Syndromes
Therapeutics
Oncogenes
Epigenomics
oncogenes
pathogenesis
Cell Survival

All Science Journal Classification (ASJC) codes

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

Cite this

Jiang, X., Hu, C., Arnovitz, S., Bugno, J., Yu, M., Zuo, Z., ... Chen, J. (2016). MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. Nature communications, 7, [11452]. https://doi.org/10.1038/ncomms11452
Jiang, Xi ; Hu, Chao ; Arnovitz, Stephen ; Bugno, Jason ; Yu, Miao ; Zuo, Zhixiang ; Chen, Ping ; Huang, Hao ; Ulrich, Bryan ; Gurbuxani, Sandeep ; Weng, Hengyou ; Strong, Jennifer ; Wang, Yungui ; Li, Yuanyuan ; Salat, Justin ; Li, Shenglai ; Elkahloun, Abdel G. ; Yang, Yang ; Neilly, Mary Beth ; Larson, Richard A. ; Le Beau, Michelle M. ; Herold, Tobias ; Bohlander, Stefan K. ; Liu, Paul P. ; Zhang, Jiwang ; Li, Zejuan ; He, Chuan ; Jin, Jie ; Hong, Seungpyo ; Chen, Jianjun. / MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. In: Nature communications. 2016 ; Vol. 7.
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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.",
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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

MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. / Jiang, Xi; Hu, Chao; Arnovitz, Stephen; Bugno, Jason; Yu, Miao; Zuo, Zhixiang; Chen, Ping; Huang, Hao; Ulrich, Bryan; Gurbuxani, Sandeep; Weng, Hengyou; Strong, Jennifer; Wang, Yungui; Li, Yuanyuan; Salat, Justin; Li, Shenglai; Elkahloun, Abdel G.; Yang, Yang; Neilly, Mary Beth; Larson, Richard A.; Le Beau, Michelle M.; Herold, Tobias; Bohlander, Stefan K.; Liu, Paul P.; Zhang, Jiwang; Li, Zejuan; He, Chuan; Jin, Jie; Hong, Seungpyo; Chen, Jianjun.

In: Nature communications, Vol. 7, 11452, 26.04.2016.

Research output: Contribution to journalArticle

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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

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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.

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