title: Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.
abstract: Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM-a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: G
authors.initials: G
authors.lastname: McNee
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Eales
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: D S
authors.initials: DS
authors.lastname: Williams
authors.affiliation: Department of Haematology, Royal Wolverhampton NHS Trust, Wolverhampton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Barkhuizen
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Bartlett
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Essex
authors.affiliation: Department of Haematology, Royal Wolverhampton NHS Trust, Wolverhampton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Anandram
authors.affiliation: Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Filer
authors.affiliation: Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: P A H
authors.initials: PA
authors.lastname: Moss
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.|Department of Haematology, University Hospitals Birmingham NHS Trust, Birmingham, UK.
authors.forename: G
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Department of Haematology, Royal Wolverhampton NHS Trust, Wolverhampton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Basu
authors.affiliation: Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: Davies
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Tennant
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D016000:Cluster Analysis; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008954:Models, Biological; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D015850:Interleukin-6