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Multiple myeloma, gammopathies

Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma

Leukemia volume 32, pages 996–1002 (2018)Cite this article

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Abstract

Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-κB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-κB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.

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Acknowledgements

This work has been supported by a grant from NIH P50−100707 (KCA, NCM), RO-1 CA050947 (KCA), and RO-1 CA 178264 (TH) and VA merit grant (I01BX001584) (NCM) and partially by the Italian Association for Cancer Research (AIRC) with ‘Special Program for Molecular Clinical Oncology–5 per mille’, 2010/15 and its Extension Program’ No. 9980, 2016/18 (PI: PT); and also by ‘Innovative Immunotherapeutic Treatments of Human Cancer’ Multi Unit Regional No. 16695 (cofinanced by AIRC and the CARICAL foundation), 2015/18 (PI: PT). KCA is an American Cancer Society Clinical Research Professor.

Author contributions

AG, TH and KCA designed research and wrote the manuscript; AG, GB, MF, TH, EM and NA performed the in vitro experiments and analyzed the data; MKS analyzed gene expression and RNA-seq data; RC performed IHC staining; JQ provided reagents and analytic tools; Y-TT and KCA provided MM patients samples; AG and EM designed, performed and analyzed in vivo experiments; NCM, PT and PT provided critical evaluation of experimental data and edited the manuscript.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA

    A Gullà, T Hideshima, G Bianchi, M Fulciniti, M Kemal Samur, J Qi, Y-T Tai, T Harada, R Carrasco, N C Munshi & K C Anderson

  2. Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy

    A Gullà, E Morelli, N Amodio, P Tagliaferri & P Tassone

  3. VA Boston Healthcare System, West Roxbury, Boston, MA, USA

    N C Munshi

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Correspondence to K C Anderson.

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Competing interests

NCM serves on advisory boards to Millennium, Celgene and Novartis. KCA serves on advisory boards Celgene, Millennium and Gilead Sciences and is a Scientific founder of OncoPep and C4 Therapeutics. All other authors declare no competing financial interests.

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Gullà, A., Hideshima, T., Bianchi, G. et al. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32, 996–1002 (2018). https://doi.org/10.1038/leu.2017.334

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