Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: In vitro and in vivo evidence

Maria T. Di Martino, Emanuela Leone, Nicola Amodio, Umberto Foresta, Marta Lionetti, Maria R. Pitari, Maria E. Gallo Cantafio, Annamaria Gullà, Francesco Conforti, Eugenio Morelli, Vera Tomaino, Marco Rossi, Massimo Negrini, Manlio Ferrarini, Michele Caraglia, Masood A. Shammas, Nikhil C. Munshi, Kenneth C. Anderson, Antonino Neri, Pierosandro TagliaferriPierfrancesco Tassone

Research output: Contribution to journalArticle


Purpose: Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. Experimental Design: Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. Results: Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. Conclusions: Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.

Original languageEnglish
Pages (from-to)6260-6270
Number of pages11
JournalClinical Cancer Research
Issue number22
Publication statusPublished - Nov 15 2012


ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Di Martino, M. T., Leone, E., Amodio, N., Foresta, U., Lionetti, M., Pitari, M. R., Gallo Cantafio, M. E., Gullà, A., Conforti, F., Morelli, E., Tomaino, V., Rossi, M., Negrini, M., Ferrarini, M., Caraglia, M., Shammas, M. A., Munshi, N. C., Anderson, K. C., Neri, A., ... Tassone, P. (2012). Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: In vitro and in vivo evidence. Clinical Cancer Research, 18(22), 6260-6270.