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Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach.
Vlummens, Philip; Verhulst, Stefaan; De Veirman, Kim; Maes, Anke; Menu, Eline; Moreaux, Jérome; De Boussac, Hugues; Robert, Nicolas; De Bruyne, Elke; Hose, Dirk; Offner, Fritz; Vanderkerken, Karin; Maes, Ken.
Afiliación
  • Vlummens P; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • Verhulst S; Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium.
  • De Veirman K; Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • Maes A; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • Menu E; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • Moreaux J; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • De Boussac H; CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Montpellier, France.
  • Robert N; Department of Biological Hematology, CHU Montpellier, Montpellier, France.
  • De Bruyne E; Institut Universitaire de France, IUF, Paris, France.
  • Hose D; CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Montpellier, France.
  • Offner F; CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biological Hematology, Montpellier, France.
  • Vanderkerken K; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • Maes K; Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Front Cell Dev Biol ; 10: 879057, 2022.
Article en En | MEDLINE | ID: mdl-35757005
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Etiology_studies / Risk_factors_studies Idioma: En Revista: Front Cell Dev Biol Año: 2022 Tipo del documento: Article País de afiliación: Bélgica

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Etiology_studies / Risk_factors_studies Idioma: En Revista: Front Cell Dev Biol Año: 2022 Tipo del documento: Article País de afiliación: Bélgica