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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

109 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 languageEnglish (US)
Article number688
JournalNature communications
Volume3
DOIs
StatePublished - 2012

ASJC Scopus subject areas

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

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