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Multiple myeloma gammopathies

Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma

Leukemia volume 34, pages 234–244 (2020)Cite this article

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Abstract

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still open questions. Herein, we investigated the functional significance of the oncogenic lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in MM. Our study demonstrates that NEAT1 expression level is higher in MM than in the majority of hematological malignancies. NEAT1 silencing by novel LNA-gapmeR antisense oligonucleotide inhibits MM cell proliferation and triggers apoptosis in vitro and in vivo murine MM model as well. By transcriptome analyses, we found that NEAT1 targeting downregulates genes involved in DNA repair processes including the Homologous Recombination pathway, which in turn results in massive DNA damage. These findings may explain the synergistic impact on apoptosis observed in MM cell lines co-treated with inhibitors of both NEAT1 and PARP. The translational significance of NEAT1 targeting is further underlined by its synergistic effects with the most common drugs administered for MM treatment, including bortezomib, carfilzomib, and melphalan. Overall, NEAT1 silencing is associated with a chemo-sensitizing effect of both conventional and novel therapies, and its targeting could therefore represent a promising strategy for novel anti-MM therapeutic options.

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Acknowledgements

This work was financially supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC) to Antonino Neri (IG16722, IG10136, and the “Special Program Molecular Clinical Oncology-5 per mille” no. 9980, 2010/15); Elisa Taiana was supported by a fellowship (#19370) from Fondazione Italiana Ricerca sul cancro (FIRC); Katia Todoerti was supported by a fellowship from Fondazione Umberto Veronesi.

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Authors and Affiliations

  1. Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy

    Elisa Taiana, Vanessa Favasuli, Domenica Ronchetti, Katia Todoerti, Martina Manzoni, Ilaria Silvestris, Luca Agnelli & Antonino Neri

  2. Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy

    Elisa Taiana, Vanessa Favasuli, Domenica Ronchetti, Katia Todoerti, Francesca Pelizzoni, Marzia Barbieri, Sonia Fabris & Antonino Neri

  3. Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy

    Maria Eugenia Gallo Cantafio, Nicola Amodio & Pierfrancesco Tassone

  4. Department of Health Sciences, University of Milan, Milan, Italy

    Natalia Platonova & Raffaella Chiaramonte

  5. Pathology Unit, Pugliese-Ciaccio Hospital, Catanzaro, Italy

    Valeria Zuccalà & Lorenza Maltese

  6. Department of Internal Medicine, DiMI, University of Genova, Genova, Italy

    Debora Soncini, Samantha Ruberti & Michele Cea

  7. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA

    Pierfrancesco Tassone

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  1. Elisa Taiana
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Correspondence to Antonino Neri.

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Taiana, E., Favasuli, V., Ronchetti, D. et al. Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma. Leukemia 34, 234–244 (2020). https://doi.org/10.1038/s41375-019-0542-5

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