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

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 a...

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Autores principales: Morelli, E, Leone, E, Cantafio, M E Gallo, Di Martino, M T, Amodio, N, Biamonte, L, Gullà, A, Foresta, U, Pitari, M R, Botta, C, Rossi, M, Neri, A, Munshi, N C, Anderson, K C, Tagliaferri, P, Tassone, P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635336/
https://www.ncbi.nlm.nih.gov/pubmed/25987254
http://dx.doi.org/10.1038/leu.2015.124
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author Morelli, E
Leone, E
Cantafio, M E Gallo
Di Martino, M T
Amodio, N
Biamonte, L
Gullà, A
Foresta, U
Pitari, M R
Botta, C
Rossi, M
Neri, A
Munshi, N C
Anderson, K C
Tagliaferri, P
Tassone, P
author_facet Morelli, E
Leone, E
Cantafio, M E Gallo
Di Martino, M T
Amodio, N
Biamonte, L
Gullà, A
Foresta, U
Pitari, M R
Botta, C
Rossi, M
Neri, A
Munshi, N C
Anderson, K C
Tagliaferri, P
Tassone, P
author_sort Morelli, E
collection PubMed
description 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.
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spelling pubmed-46353362015-11-25 Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo Morelli, E Leone, E Cantafio, M E Gallo Di Martino, M T Amodio, N Biamonte, L Gullà, A Foresta, U Pitari, M R Botta, C Rossi, M Neri, A Munshi, N C Anderson, K C Tagliaferri, P Tassone, P Leukemia Original Article 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. Nature Publishing Group 2015-11 2015-07-07 /pmc/articles/PMC4635336/ /pubmed/25987254 http://dx.doi.org/10.1038/leu.2015.124 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Morelli, E
Leone, E
Cantafio, M E Gallo
Di Martino, M T
Amodio, N
Biamonte, L
Gullà, A
Foresta, U
Pitari, M R
Botta, C
Rossi, M
Neri, A
Munshi, N C
Anderson, K C
Tagliaferri, P
Tassone, P
Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title_full Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title_fullStr Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title_full_unstemmed Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title_short Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
title_sort selective targeting of irf4 by synthetic microrna-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635336/
https://www.ncbi.nlm.nih.gov/pubmed/25987254
http://dx.doi.org/10.1038/leu.2015.124
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