Research Papers:

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, Melissa Sorci, Silvia Masciarelli, Simone Larivera, Ivano Legnini, Ilaria Iosue, Irene Bozzoni, Francesco Fazi and Alessandro Fatica _

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Oncotarget. 2016; 7:60155-60168. https://doi.org/10.18632/oncotarget.11165

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Arianna Mangiavacchi1,5,*, Melissa Sorci1,*, Silvia Masciarelli2, Simone Larivera1, Ivano Legnini1, Ilaria Iosue2, Irene Bozzoni1,3,4, Francesco Fazi2, Alessandro Fatica1

1Department of Biology and Biotechnology “C. Darwiny”, Sapienza University of Rome, Rome, 00185, Italy

2Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, 00185, Italy

3Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, 00161, Italy

4Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, 00185, Italy

5Present 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: [email protected]

Keywords: long non-coding RNA, miR-125, acute myeloid leukemia, IRF4

Received: November 13, 2015     Accepted: July 26, 2016     Published: August 09, 2016


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.

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