%0 Journal Article
%T Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation
%A A. R. R. Forrest
%A M. Kanamori-Katayama
%A Y. Tomaru
%A T. Lassmann
%A N. Ninomiya
%A Y. Takahashi
%A M. J. L. de Hoon
%A A. Kubosaki
%A A. Kaiho
%A M. Suzuki
%A J. Yasuda
%A J. Kawai
%A Y. Hayashizaki
%A D. A. Hume
%A H. Suzuki
%J Quantitative Biology
%D 2010
%I arXiv
%R 10.1038/leu.2009.246
%X 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 micro- RNAs (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 prodifferentiative 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.
%U http://arxiv.org/abs/1007.2689v1