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

72 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)

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10.1038/ncomms11452

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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, 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, [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 journal › Article

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

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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AU - Chen, Ping

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AU - Ulrich, Bryan

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AU - Strong, Jennifer

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AU - Li, Yuanyuan

AU - Salat, Justin

AU - Li, Shenglai

AU - Elkahloun, Abdel G.

AU - Yang, Yang

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AU - Larson, Richard A.

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AU - Herold, Tobias

AU - Bohlander, Stefan K.

AU - Liu, Paul P.

AU - Zhang, Jiwang

AU - Li, Zejuan

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AU - Jin, Jie

AU - Hong, Seungpyo

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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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