title: Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation.
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.
authors: LSA Technology Development Unit, Omics Science Center, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan. alistair.forrest@gmail.com
authors: A R R
authors: AR
authors: Forrest
authors: M
authors: M
authors: Kanamori-Katayama
authors: Y
authors: Y
authors: Tomaru
authors: T
authors: T
authors: Lassmann
authors: N
authors: N
authors: Ninomiya
authors: Y
authors: Y
authors: Takahashi
authors: M J L
authors: MJ
authors: de Hoon
authors: A
authors: A
authors: Kubosaki
authors: A
authors: A
authors: Kaiho
authors: M
authors: M
authors: Suzuki
authors: J
authors: J
authors: Yasuda
authors: J
authors: J
authors: Kawai
authors: Y
authors: Y
authors: Hayashizaki
authors: D A
authors: DA
authors: Hume
authors: H
authors: H
authors: Suzuki
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009000:Monocytes / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D035683:MicroRNAs; D013755:Tetradecanoylphorbol Acetate; C524942:MIRN155 microRNA, human; C525710:MIR222, human; C545473:MIRN503 microRNA, human