The miR-223 host non-coding transcript linc-223 induces IRF4 expression in acute myeloid leukemia by acting as a competing endogenous RNA

// Arianna Mangiavacchi 1, 5, * , Melissa Sorci 1, * , Silvia Masciarelli 2 , Simone Larivera 1 , Ivano Legnini 1 , Ilaria Iosue 2 , Irene Bozzoni 1, 3, 4 , Francesco Fazi 2 , Alessandro Fatica 1 1 Department of Biology and Biotechnology “C. Darwiny”, Sapienza University of Rome, Rome, 00185, Italy 2 Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, 00185, Italy 3 Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, 00161, Italy 4 Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, 00185, Italy 5 Present address: KAUST Environmental Epigenetics Research Program, Biological Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia * These authors contributed equally to this work Correspondence to: Alessandro Fatica, email: alessandro.fatica@uniroma1.it Keywords: long non-coding RNA, miR-125, acute myeloid leukemia, IRF4 Received: November 13, 2015      Accepted: July 26, 2016      Published: August 09, 2016 ABSTRACT Alterations in genetic programs required for terminal myeloid differentiation and aberrant proliferation characterize acute myeloid leukemia (AML) cells. Here, we identify the host transcript of miR-223, linc-223, as a novel functional long non-coding RNA (lncRNA) in AML. We show that from the primary nuclear transcript, the alternative production of miR-223 and linc-223 is finely regulated during monocytic differentiation. Moreover, linc-223 expression inhibits cell cycle progression and promotes monocytic differentiation of AML cells. We also demonstrate that endogenous linc-223 localizes in the cytoplasm and acts as a competing endogenous RNA for miR-125-5p, an oncogenic microRNA in leukemia. In particular, we show that linc-223 directly binds to miR-125-5p and that its knockdown increases the repressing activity of miR-125-5p resulting in the downregulation of its target interferon regulatory factor 4 (IRF4), which it was previously shown to inhibit the oncogenic activity of miR-125-5p in vivo . Furthermore, data from primary AML samples show significant downregulation of linc-223 in different AML subtypes. Therein, these findings indicate that the newly identified lncRNA linc-223 may have an important role in myeloid differentiation and leukemogenesis, at least in part, by cross-talking with IRF4 mRNA.