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

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, D. A. Hume, H. Suzuki

Research output: Contribution to journalArticlepeer-review

192 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)460-466
Number of pages7
JournalLeukemia
Volume24
Issue number2
DOIs
Publication statusPublished - 2010 Feb
Externally publishedYes

Keywords

  • AML
  • Acute myeloid leukemia
  • Differentiation
  • MicroRNA
  • Monocyte
  • Systems biology

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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