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, Alessandro Fatica

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.
Original languageEnglish (US)
Pages (from-to)60155-60168
Number of pages14
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - Aug 9 2016

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: The authors would like to thank Dr A. Rosa and Dr A. Brivanlou for the ePiggyBac inducible transposon system, A Sorrentino for the RNA from the human CD34+ progenitor cells, and M. Marchioni and M. Arceci for technical assistance. This work was supported by A.I.R.C. (IG 17352) and “Progetti Ateneo” Sapienza University of Rome to A.F.; and ERC-2013 (AdG 340172–MUNCODD), Epigen-Epigenomics Flagship Project, AFM-Telethon (17835), PRIN 2013, AriSLA full grant 2014 “ARCI” and HFSP (RGP0009/2014) to I.B. Contribution of AIRC (StG 4841) and FILAS-RU-2014-1020 to FF was greatly appreciated.

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