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Differentiation

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Leukemia volume 24, pages 460–466 (2010)Cite this article

Abstract

Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced microRNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these pro-differentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.

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Acknowledgements

This study was supported by the following: a research grant for RIKEN Omics Science Center from MEXT to YH and a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan to YH (http://genomenetwork.nig.ac.jp/index_e.html). We also thank all of the members in the FANTOM consortium for fruitful collaboration and cooperation, in particular thanks to F. Hori for information collection and C Wells and J Quackenbush for discussions on the microRNA microarrays. ARRF was supported by a CJ Martin Fellowship from the Australian NHMRC (ID 428261).

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Authors and Affiliations

  1. LSA Technology Development Unit, Omics Science Center, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan

    A R R Forrest, M Kanamori-Katayama, Y Tomaru, T Lassmann, N Ninomiya, Y Takahashi, M J L de Hoon, A Kubosaki, A Kaiho, M Suzuki, J Yasuda, J Kawai, Y Hayashizaki & H Suzuki

  2. The Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia

    A R R Forrest

  3. The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, UK

    D A Hume

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  1. A R R Forrest
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Correspondence to A R R Forrest.

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Forrest, A., Kanamori-Katayama, M., Tomaru, Y. et al. Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation. Leukemia 24, 460–466 (2010). https://doi.org/10.1038/leu.2009.246

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