MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

Zejuan Li; Hao Huang; Ping Chen; Miao He; Yuanyuan Li; Stephen Arnovitz; Xi Jiang; Chunjiang He; Elizabeth Hyjek; Jun Zhang; Zhiyu Zhang; Abdel Elkahloun; Donglin Cao; Chen Shen; Mark Wunderlich; Yungui Wang; Mary Beth Neilly; Jie Jin; Minjie Wei; Jun Lu; Peter J.M. Valk; Ruud Delwel; Bob Lowenberg; Michelle M. Le Beau; James Vardiman; James C. Mulloy; Nancy J. Zeleznik-Le; Paul P. Liu; Jiwang Zhang; Jianjun Chen

doi:10.1038/ncomms1681

MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

Zejuan Li, Hao Huang, Ping Chen, Miao He, Yuanyuan Li, Stephen Arnovitz, Xi Jiang, Chunjiang He, Elizabeth Hyjek, Jun Zhang, Zhiyu Zhang, Abdel Elkahloun, Donglin Cao, Chen Shen, Mark Wunderlich, Yungui Wang, Mary Beth Neilly, Jie Jin, Minjie Wei, Jun LuPeter J.M. Valk, Ruud Delwel, Bob Lowenberg, Michelle M. Le Beau, James Vardiman, James C. Mulloy, Nancy J. Zeleznik-Le, Paul P. Liu, Jiwang Zhang, Jianjun Chen

Research output: Contribution to journal › Article

110 Scopus citations

Abstract

HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

Original language	English (US)
Article number	688
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1681
State	Published - 2012

ASJC Scopus subject areas

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

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Li, Z., Huang, H., Chen, P., He, M., Li, Y., Arnovitz, S., Jiang, X., He, C., Hyjek, E., Zhang, J., Zhang, Z., Elkahloun, A., Cao, D., Shen, C., Wunderlich, M., Wang, Y., Neilly, M. B., Jin, J., Wei, M., ... Chen, J. (2012). MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nature Communications, 3, [688]. https://doi.org/10.1038/ncomms1681

MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. / Li, Zejuan; Huang, Hao; Chen, Ping; He, Miao; Li, Yuanyuan; Arnovitz, Stephen; Jiang, Xi; He, Chunjiang; Hyjek, Elizabeth; Zhang, Jun; Zhang, Zhiyu; Elkahloun, Abdel; Cao, Donglin; Shen, Chen; Wunderlich, Mark; Wang, Yungui; Neilly, Mary Beth; Jin, Jie; Wei, Minjie; Lu, Jun; Valk, Peter J.M.; Delwel, Ruud; Lowenberg, Bob; Le Beau, Michelle M.; Vardiman, James; Mulloy, James C.; Zeleznik-Le, Nancy J.; Liu, Paul P.; Zhang, Jiwang; Chen, Jianjun.

In: Nature Communications, Vol. 3, 688, 2012.

Research output: Contribution to journal › Article

Li, Z, Huang, H, Chen, P, He, M, Li, Y, Arnovitz, S, Jiang, X, He, C, Hyjek, E, Zhang, J, Zhang, Z, Elkahloun, A, Cao, D, Shen, C, Wunderlich, M, Wang, Y, Neilly, MB, Jin, J, Wei, M, Lu, J, Valk, PJM, Delwel, R, Lowenberg, B, Le Beau, MM, Vardiman, J, Mulloy, JC, Zeleznik-Le, NJ, Liu, PP, Zhang, J & Chen, J 2012, 'MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia', Nature Communications, vol. 3, 688. https://doi.org/10.1038/ncomms1681

Li, Zejuan ; Huang, Hao ; Chen, Ping ; He, Miao ; Li, Yuanyuan ; Arnovitz, Stephen ; Jiang, Xi ; He, Chunjiang ; Hyjek, Elizabeth ; Zhang, Jun ; Zhang, Zhiyu ; Elkahloun, Abdel ; Cao, Donglin ; Shen, Chen ; Wunderlich, Mark ; Wang, Yungui ; Neilly, Mary Beth ; Jin, Jie ; Wei, Minjie ; Lu, Jun ; Valk, Peter J.M. ; Delwel, Ruud ; Lowenberg, Bob ; Le Beau, Michelle M. ; Vardiman, James ; Mulloy, James C. ; Zeleznik-Le, Nancy J. ; Liu, Paul P. ; Zhang, Jiwang ; Chen, Jianjun. / MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. In: Nature Communications. 2012 ; Vol. 3.

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title = "MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia",

abstract = "HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.",

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AU - Huang, Hao

AU - Chen, Ping

AU - He, Miao

AU - Li, Yuanyuan

AU - Arnovitz, Stephen

AU - Jiang, Xi

AU - He, Chunjiang

AU - Hyjek, Elizabeth

AU - Zhang, Jun

AU - Zhang, Zhiyu

AU - Elkahloun, Abdel

AU - Cao, Donglin

AU - Shen, Chen

AU - Wunderlich, Mark

AU - Wang, Yungui

AU - Neilly, Mary Beth

AU - Jin, Jie

AU - Wei, Minjie

AU - Lu, Jun

AU - Valk, Peter J.M.

AU - Delwel, Ruud

AU - Lowenberg, Bob

AU - Le Beau, Michelle M.

AU - Vardiman, James

AU - Mulloy, James C.

AU - Zeleznik-Le, Nancy J.

AU - Liu, Paul P.

AU - Zhang, Jiwang

AU - Chen, Jianjun

PY - 2012

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N2 - HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

AB - HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

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