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

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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

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms1681

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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, Article 688. https://doi.org/10.1038/ncomms1681

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

@article{4d5dac0697c34a14b258dc6a108b15f7,

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.",

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

note = "Funding Information: We thank Dr. Janet D. Rowley and Colles Price for their constructive suggestions and comments, and Drs Gang Huang, Long Zhang and Roger Luo for their technical support on isolation and retroviral transduction of mouse foetal liver cells, mouse tail vein injection and general mouse BM transplantation assays. We are also grateful to Drs Gregory Hannon, Scott Hammond, Lin He, Scott Armstrong and Michael Thirman for providing retroviral constructs. This work was supported in part by the National Institutes of Health (NIH) R01 grant CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), LLS Special Fellowship (Z.L.), Gabrielle{\textquoteright}s Angel Fondation for Cancer Research (J.C.; Z.L.; H.H.), Leukemia and Lymphoma Society (LLS) Translational Research Grant (J.C.), Fidelity Foundation (J.C.), NIH R01 CA118319 Sub-Award (J.C.M. and J.C.), R01 HL95896 (J.Z.), HL087188 (N.J.Z.-L.), Intramural Research Program of National Human Genome Research Institute, NIH (A.E. and P.P.L.), NIH P01 CA40046 (M.M.L.B) and P30 CA014599 (CCSG) (M.M.L.B). J.C.M. is a Leukemia and Lymphoma Society (LLS) Scholar.",

year = "2012",

doi = "10.1038/ncomms1681",

language = "English (US)",

volume = "3",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

T1 - MiR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

AU - Li, Zejuan

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

N1 - Funding Information: We thank Dr. Janet D. Rowley and Colles Price for their constructive suggestions and comments, and Drs Gang Huang, Long Zhang and Roger Luo for their technical support on isolation and retroviral transduction of mouse foetal liver cells, mouse tail vein injection and general mouse BM transplantation assays. We are also grateful to Drs Gregory Hannon, Scott Hammond, Lin He, Scott Armstrong and Michael Thirman for providing retroviral constructs. This work was supported in part by the National Institutes of Health (NIH) R01 grant CA127277 (J.C.), American Cancer Society (ACS) Research Scholar grant (J.C.), LLS Special Fellowship (Z.L.), Gabrielle’s Angel Fondation for Cancer Research (J.C.; Z.L.; H.H.), Leukemia and Lymphoma Society (LLS) Translational Research Grant (J.C.), Fidelity Foundation (J.C.), NIH R01 CA118319 Sub-Award (J.C.M. and J.C.), R01 HL95896 (J.Z.), HL087188 (N.J.Z.-L.), Intramural Research Program of National Human Genome Research Institute, NIH (A.E. and P.P.L.), NIH P01 CA40046 (M.M.L.B) and P30 CA014599 (CCSG) (M.M.L.B). J.C.M. is a Leukemia and Lymphoma Society (LLS) Scholar.

PY - 2012

Y1 - 2012

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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U2 - 10.1038/ncomms1681

DO - 10.1038/ncomms1681

M3 - Article

C2 - 22353710

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

M1 - 688

ER -

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

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