Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach

Philip Vlummens; Stefaan Verhulst; Kim De Veirman; Anke Maes; Eline Menu; Jérome Moreaux; Hugues De Boussac; Nicolas Robert; Elke De Bruyne; Dirk Hose; Fritz Offner; Karin Vanderkerken; Ken Maes

doi:10.3389/fcell.2022.879057

Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach

Front Cell Dev Biol. 2022 Jun 8:10:879057. doi: 10.3389/fcell.2022.879057. eCollection 2022.

Authors

Philip Vlummens^{1

2}, Stefaan Verhulst³, Kim De Veirman¹, Anke Maes¹, Eline Menu¹, Jérome Moreaux^{4

5

6}, Hugues De Boussac⁴, Nicolas Robert⁴, Elke De Bruyne¹, Dirk Hose¹, Fritz Offner², Karin Vanderkerken¹, Ken Maes^{1

7}

Affiliations

¹ Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
² Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium.
³ Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
⁴ CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Montpellier, France.
⁵ Department of Biological Hematology, CHU Montpellier, Montpellier, France.
⁶ Institut Universitaire de France, IUF, Paris, France.
⁷ Center for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ), Brussels, Belgium.

Abstract

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Subsets of patients have high-risk features linked with dismal outcome. Therefore, the need for effective therapeutic options remains high. Here, we used bio-informatic tools to identify novel targets involved in DNA repair and epigenetics and which are associated with high-risk myeloma. The prognostic significance of the target genes was analyzed using publicly available gene expression data of MM patients (TT2/3 and HM cohorts). Hence, protein arginine methyltransferase 5 (PRMT5) was identified as a promising target. Druggability was assessed in OPM2, JJN3, AMO1 and XG7 human myeloma cell lines using the PRMT5-inhibitor EPZ015938. EPZ015938 strongly reduced the total symmetric-dimethyl arginine levels in all cell lines and lead to decreased cellular growth, supported by cell line dependent changes in cell cycle distribution. At later time points, apoptosis occurred, as evidenced by increased AnnexinV-positivity and cleavage of PARP and caspases. Transcriptome analysis revealed a role for PRMT5 in regulating alternative splicing, nonsense-mediated decay, DNA repair and PI3K/mTOR-signaling, irrespective of the cell line type. PRMT5 inhibition reduced the expression of upstream DNA repair kinases ATM and ATR, which may in part explain our observation that EPZ015938 and the DNA-alkylating agent, melphalan, have combinatory effects. Of interest, using a low-dose of mTOR-inhibitor, we observed that cell viability was partially rescued from the effects of EPZ015938, indicating a role for mTOR-related pathways in the anti-myeloma activity of EPZ015938. Moreover, PRMT5 was shown to be involved in splicing regulation of MMSET and SLAMF7, known genes of importance in MM disease. As such, we broaden the understanding of the exact role of PRMT5 in MM disease and further underline its use as a possible therapeutic target.

Keywords: DNA repair; PRMT5; RNA splicing; epigenetics; myeloma.