Molecular signature associated with cladribine treatment in patients with multiple sclerosis
IntroductionLittle is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233546/full |
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| author | Nicolas Fissolo Laura Calvo-Barreiro Herena Eixarch Ursula Boschert Luisa M. Villar Lucienne Costa-Frossard Mireia Ferrer Alex Sanchez Alex Sanchez Eva Borràs Eva Borràs Eduard Sabidó Eduard Sabidó Carmen Espejo Xavier Montalban Manuel Comabella |
| author_facet | Nicolas Fissolo Laura Calvo-Barreiro Herena Eixarch Ursula Boschert Luisa M. Villar Lucienne Costa-Frossard Mireia Ferrer Alex Sanchez Alex Sanchez Eva Borràs Eva Borràs Eduard Sabidó Eduard Sabidó Carmen Espejo Xavier Montalban Manuel Comabella |
| author_sort | Nicolas Fissolo |
| collection | DOAJ |
| description | IntroductionLittle is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment response biomarkers to cladribine in patients with MS.MethodsGene, protein and microRNA (miRNA) expression profiles were determined by microarrays (genes, miRNAs) and mass spectrometry (proteins) in peripheral blood mononuclear cells (PBMCs) from MS patients after in vitro treatment with cladribine in its active and inactive forms. Two bioinformatics approaches to integrate the three obtained datasets were applied: (i) a multiomics discriminant analysis (DIABLO - Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies); and (ii) a multi-stage integration of features selected in differential expression analysis on each dataset and then merged. Selected molecules from the in vitro study were quantified by qPCR ex vivo in PBMCs from MS patients receiving cladribine.ResultsPBMCs treated in vitro with cladribine were characterized by a major downregulation of gene, protein, and miRNA expression compared with the untreated cells. An intermediate pattern between the cladribine-treated and untreated conditions was observed in PBMCs treated with cladribine in its inactive form. The differential expression analysis of each dataset led to the identification of four genes and their encoded proteins, and twenty-two miRNAs regulating their expression, that were associated with cladribine treatment. Two of these genes (PPIF and NHLRC2), and three miRNAs (miR-21-5p, miR-30b-5p, and miR-30e-5p) were validated ex vivo in MS patients treated with cladribine.DiscussionBy using a combination of omics data and bioinformatics approaches we were able to identify a multiomics molecular profile induced by cladribine in vitro in PBMCs. We also identified a number of biomarkers that were validated ex vivo in PBMCs from patients with MS treated with cladribine that have the potential to become treatment response biomarkers to this drug. |
| first_indexed | 2024-03-12T21:55:15Z |
| format | Article |
| id | doaj.art-9035da7161674ce99a2b2cd80d00a33e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T21:55:15Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9035da7161674ce99a2b2cd80d00a33e2023-07-25T17:54:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-07-011410.3389/fimmu.2023.12335461233546Molecular signature associated with cladribine treatment in patients with multiple sclerosisNicolas Fissolo0Laura Calvo-Barreiro1Herena Eixarch2Ursula Boschert3Luisa M. Villar4Lucienne Costa-Frossard5Mireia Ferrer6Alex Sanchez7Alex Sanchez8Eva Borràs9Eva Borràs10Eduard Sabidó11Eduard Sabidó12Carmen Espejo13Xavier Montalban14Manuel Comabella15Servei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainServei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainServei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainAres Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, GermanyDepartment of Immunology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainDepartment of Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainStatistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, SpainStatistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, SpainGenetics, Microbiology and Statistics Department, Universitat de Barcelona, Barcelona, SpainProteomics Unit, Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, SpainProteomics Unit, Universitat Pompeu Fabra, Barcelona, SpainProteomics Unit, Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, SpainProteomics Unit, Universitat Pompeu Fabra, Barcelona, SpainServei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainServei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainServei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat) Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, SpainIntroductionLittle is known about the molecular profiling associated with the effect of cladribine in patients with multiple sclerosis (MS). Here, we aimed first to characterize the transcriptomic and proteomic profiles induced by cladribine in blood cells, and second to identify potential treatment response biomarkers to cladribine in patients with MS.MethodsGene, protein and microRNA (miRNA) expression profiles were determined by microarrays (genes, miRNAs) and mass spectrometry (proteins) in peripheral blood mononuclear cells (PBMCs) from MS patients after in vitro treatment with cladribine in its active and inactive forms. Two bioinformatics approaches to integrate the three obtained datasets were applied: (i) a multiomics discriminant analysis (DIABLO - Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies); and (ii) a multi-stage integration of features selected in differential expression analysis on each dataset and then merged. Selected molecules from the in vitro study were quantified by qPCR ex vivo in PBMCs from MS patients receiving cladribine.ResultsPBMCs treated in vitro with cladribine were characterized by a major downregulation of gene, protein, and miRNA expression compared with the untreated cells. An intermediate pattern between the cladribine-treated and untreated conditions was observed in PBMCs treated with cladribine in its inactive form. The differential expression analysis of each dataset led to the identification of four genes and their encoded proteins, and twenty-two miRNAs regulating their expression, that were associated with cladribine treatment. Two of these genes (PPIF and NHLRC2), and three miRNAs (miR-21-5p, miR-30b-5p, and miR-30e-5p) were validated ex vivo in MS patients treated with cladribine.DiscussionBy using a combination of omics data and bioinformatics approaches we were able to identify a multiomics molecular profile induced by cladribine in vitro in PBMCs. We also identified a number of biomarkers that were validated ex vivo in PBMCs from patients with MS treated with cladribine that have the potential to become treatment response biomarkers to this drug.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233546/fullmultiple sclerosiscladribinebiomarkersomicsbioinformatics |
| spellingShingle | Nicolas Fissolo Laura Calvo-Barreiro Herena Eixarch Ursula Boschert Luisa M. Villar Lucienne Costa-Frossard Mireia Ferrer Alex Sanchez Alex Sanchez Eva Borràs Eva Borràs Eduard Sabidó Eduard Sabidó Carmen Espejo Xavier Montalban Manuel Comabella Molecular signature associated with cladribine treatment in patients with multiple sclerosis Frontiers in Immunology multiple sclerosis cladribine biomarkers omics bioinformatics |
| title | Molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| title_full | Molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| title_fullStr | Molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| title_full_unstemmed | Molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| title_short | Molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| title_sort | molecular signature associated with cladribine treatment in patients with multiple sclerosis |
| topic | multiple sclerosis cladribine biomarkers omics bioinformatics |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233546/full |
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