Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma.

Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe clinical manifestations and poor prognosis, particularly in relapsed/refractory cases. Identifying novel therapeutic targets is crucial to improve treatment outcomes in these patients. In this study, we investigated the role of the protein arginine methyltransferase 1 (PRMT1) in MM pathogenesis and explored its potential as a therapeutic target. We observed that PRMT1, responsible for most asymmetric di-methylation in cells, exhibited the highest expression among PRMT family members in MM cell lines and primary MM cells. Importantly, PRMT1 expression was significantly elevated in relapsed/refractory patients compared to newly diagnosed patients. High expression of PRMT1 expression was strongly associated with poor prognosis. We found that genetic or enzymatic inhibition of PRMT1 impaired MM cell growth, induced cell cycle arrest, and triggered cell death. Treatment with MS023, a potent PRMT type I inhibitor, demonstrated a robust inhibitory effect on the viability of primary cells isolated from newly diagnosed and proteasome inhibitor-relapsed/refractory patients in a dose-dependent manner. Suppression of PRMT1 downregulated genes related to cell division and upregulated genes associated with apoptosis pathway. We also found that genes related to immune response and lymphocyte activation were significantly upregulated in PRMT1-suppressed cells. Notably, the activation status of T cells was strikingly enhanced upon co-culturing with PRMT1-KO MM cells.

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Copyright © 2023 Nguyen, Le, Liu, Cesarano, DiMeo, Perna, Kapur, Walker and Tran.

Déclaration de conflit d'intérêts

Author BW reports unrelated grants from Bristol Myers Squibb, Genentech, and Leukemia and Lymphoma Society during the conduct of the study. Author NTT is an inventor on a patent application related to this work filed by the MDC European patent application no. 21192657.1-1111, filed 23 August 2021. The patent is not related to the works in the manuscript. Author FP is an inventor on patents related to adoptive cell therapies, held by Memorial Sloan Kettering Cancer Center some licensed to Takeda and Indiana University. Research funding from Lonza and NGMBiopharmaceuticals. Scientific advisory board for BioLegend and Orbitaltx Indiana. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.