Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo

Cirino Botta, Amodio, Kenneth C. Anderson, Maria Teresa Di Martino, Foresta, Cirino Botta, Emanuela Leone, Pitari, Eugenio Morelli, Annamaria Gullà, M E Gallo Cantafio, M E Gallo Cantafio, Biamonte, Rossi, Neri, Pierfrancesco Tassone, Munshi, Pierosandro Tagliaferri

Risultato della ricerca: Articlepeer review

77 Citazioni (Scopus)

Abstract

Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.
Lingua originaleEnglish
pagine (da-a)2173-2183
Numero di pagine11
RivistaLeukemia
Volume29
Stato di pubblicazionePublished - 2015

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.2700.2730???
  • ???subjectarea.asjc.1300.1306???

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