Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma
Open accessAbstract
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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PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.
“More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [176]
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The roles of DNA, RNA and histone methylation in ageing and cancer
Michalak, E. M., Burr, M. L., Bannister, A. J., & Dawson, M. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0143-1 · Cited by 549 · see citing works
- Authors
- Gullà, A., Hideshima, T., Bianchi, G., Fulciniti, M., Kemal Samur, M., Qi, J., Tai, Y.-T., Harada, T., Morelli, E., Amodio, N., Carrasco, R., Tagliaferri, P., Munshi, N. C., Tassone, P., & Anderson, K. C.
- Affiliations
- Magna Graecia University (IT)
- Dana-Farber Cancer Institute (US)
- VA Boston Healthcare System (US)
- Corresponding author
- Anderson, K C
- ORCID
- Venue
- Leukemia
- Published
- 2017-11-21
- Volume
- 32
- Issue
- 4
- Pages
- 996-1002
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- PMC
- PMC5871539
- OpenAlex
- W2769020200
- Cited by
- 102
- References
- 42
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 14 · 2022: 15 · 2021: 21 · 2020: 12 · 2019: 11 · 2018: 6
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001584)
- National Institutes of Health (5r01ca178264-05)
- National Cancer Institute (R01-CA178264, P50CA100707, R01CA050947, R01CA207237, P01CA155258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- PRMT5, multiple myeloma, PRMT5 inhibition, TRIM21, NF-κB signaling, prognostic factors, therapeutic target, survival outcomes, oral administration
- MeSH terms
- Animals, Humans, Isoquinolines, Multiple Myeloma, Prognosis, Protein-Arginine N-Methyltransferases, Pyrimidines, Ribonucleoproteins, Signal Transduction, NF-kappa B, Cell Line, Tumor, Cell Proliferation
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