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

E. Morelli, E. Leone, M. E Gallo Cantafio, M. T. Di Martino, N. Amodio, L. Biamonte, A. Gullà, U. Foresta, M. R. Pitari, C. Botta, M. Rossi, A. Neri, N. C. Munshi, K. C. Anderson, P. Tagliaferri, P. Tassone

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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.

Original languageEnglish
Pages (from-to)2173-2183
Number of pages11
JournalLeukemia
Volume29
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Multiple Myeloma
MicroRNAs
Down-Regulation
Caspase 10
In Vitro Techniques
interferon regulatory factor-4
Neoplasms
Inbred NOD Mouse
Survival
Autophagy
Hematologic Neoplasms
Mesenchymal Stromal Cells
Heterografts
Transfection
Cell Death
Clinical Trials
Cell Line
Messenger RNA
Growth

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Morelli, E., Leone, E., Cantafio, M. E. G., Di Martino, M. T., Amodio, N., Biamonte, L., ... Tassone, P. (2015). Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo. Leukemia, 29(11), 2173-2183. https://doi.org/10.1038/leu.2015.124

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.

In: Leukemia, Vol. 29, No. 11, 01.11.2015, p. 2173-2183.

Research output: Contribution to journalArticle

Morelli, E, Leone, E, Cantafio, MEG, Di Martino, MT, Amodio, N, Biamonte, L, Gullà, A, Foresta, U, Pitari, MR, Botta, C, Rossi, M, Neri, A, Munshi, NC, Anderson, KC, Tagliaferri, P & Tassone, P 2015, 'Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo', Leukemia, vol. 29, no. 11, pp. 2173-2183. https://doi.org/10.1038/leu.2015.124
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. In: Leukemia. 2015 ; Vol. 29, No. 11. pp. 2173-2183.
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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.",
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AU - Amodio, N.

AU - Biamonte, L.

AU - Gullà, A.

AU - Foresta, U.

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AU - Botta, C.

AU - Rossi, M.

AU - Neri, A.

AU - Munshi, N. C.

AU - Anderson, K. C.

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AU - Tassone, P.

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