Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma

Gavin McNee, Katherine Eales, Wenbin Wei, Deborah Williams, Angelique Barkhuizen, David Bartlett, Sarah Essex, Seetharam Anandram, Andrew Filer, Paul Moss, Guy Pratt, Supratik Basu, Clare Davies, Daniel Tennant

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)
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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 survival 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 (IL-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.w
Original languageEnglish
Pages (from-to)373-381
Issue number2
Early online date11 Jul 2016
Publication statusPublished - Feb 2017


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