title: Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo.
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.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Leone
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: M E Gallo
authors.initials: ME
authors.lastname: Cantafio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Biamonte
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gullà
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Foresta
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Pitari
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Botta
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Medical Sciences, University of Milan, Hematology 1, IRCCS Policlinico Foundation, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Neri
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|VA Boston Healthcare System, West Roxbury, Boston, MA, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D035683:MicroRNAs; D000099218:Interferon Regulatory Factor-4; C531888:MIRN125 microRNA, human