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 and Jianjun Chen ()
Additional contact information
Zejuan Li: University of Chicago
Hao Huang: University of Chicago
Ping Chen: University of Chicago
Miao He: University of Chicago
Yuanyuan Li: University of Chicago
Stephen Arnovitz: University of Chicago
Xi Jiang: University of Chicago
Chunjiang He: University of Chicago
Elizabeth Hyjek: University of Chicago
Jun Zhang: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center
Zhiyu Zhang: Tang Center for Herbal Medicine Research, University of Chicago
Abdel Elkahloun: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH
Donglin Cao: University of Chicago
Chen Shen: University of Chicago
Mark Wunderlich: Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Yungui Wang: Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine
Mary Beth Neilly: University of Chicago
Jie Jin: Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine
Minjie Wei: China Medical University
Jun Lu: Yale Stem Cell Center, Yale University
Peter J.M. Valk: Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Ruud Delwel: Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Bob Lowenberg: Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Michelle M. Le Beau: University of Chicago
James Vardiman: University of Chicago
James C. Mulloy: Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Nancy J. Zeleznik-Le: Loyola University Medical Center
Paul P. Liu: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH
Jiwang Zhang: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center
Jianjun Chen: University of Chicago

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1681

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