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

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow in order to survive and proliferate. Interactions between the malignant plasma cell and bone marrow mesenchymal stem cell (BMMSC) are thought to be a critical determinant of this requirement, and include both physical and chemical components. There is increasing evidence that the phenotype of the BMMSC is stably altered in patients with MM. More recently, it has been suggested that this phenotypic transformation is also observed in patients with the benign condition known as monoclonal gammopathy of undetermined significance (MGUS), which almost always precedes MM. In this study, we describe a mechanism by which the peptidyl arginine deiminase 2 (PADI2) enzyme plays an key role in the control of malignant plasma cell phenotype by BMMSCs. PADI enzymes deiminate (citrullinate) peptidyl arginine residues, changing the function or interactions made by the target protein. We identified PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through citrullination of arginine residue 26 of histone H3, it induces the upregulation of interleukin-6 (IL-6) expression. This directly 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.

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McNee G, Eales KL, Wei W, Williams DS, Barkhuizen A, Bartlett DB, Essex S, Anandram S, Filer A, Moss PA, Pratt G, Basu S, Davies CC, Tennant DA