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

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 epi...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213887/
https://www.ncbi.nlm.nih.gov/pubmed/35757005
http://dx.doi.org/10.3389/fcell.2022.879057
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author 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
author_facet 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
author_sort Vlummens, Philip
collection PubMed
description 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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spelling pubmed-92138872022-06-23 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 Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2022-06-08 /pmc/articles/PMC9213887/ /pubmed/35757005 http://dx.doi.org/10.3389/fcell.2022.879057 Text en Copyright © 2022 Vlummens, Verhulst, De Veirman, Maes, Menu, Moreaux, De Boussac, Robert, De Bruyne, Hose, Offner, Vanderkerken and Maes. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
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
Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title_full Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title_fullStr Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title_full_unstemmed Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title_short Inhibition of the Protein Arginine Methyltransferase PRMT5 in High-Risk Multiple Myeloma as a Novel Treatment Approach
title_sort inhibition of the protein arginine methyltransferase prmt5 in high-risk multiple myeloma as a novel treatment approach
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213887/
https://www.ncbi.nlm.nih.gov/pubmed/35757005
http://dx.doi.org/10.3389/fcell.2022.879057
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