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

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.

Citation
Mangiavacchi A, Sorci M, Masciarelli S, Larivera S, Legnini I, et al. (2016) The miR-223 host non-coding transcript linc-223 induces IRF4 expression in acute myeloid leukemia by acting as a competing endogenous RNA. Oncotarget. Available: http://dx.doi.org/10.18632/oncotarget.11165.

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.

Publisher
Impact Journals, LLC

Journal
Oncotarget

DOI
10.18632/oncotarget.11165

PubMed ID
27517498

Additional Links
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=11165

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