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.
Highlights
Multiple myeloma (MM) is a malignant disease of plasma cells within the bone marrow that, despite improving survival, remains incurable meaning an urgent requirement for novel therapies.One characteristic feature of MM is that a pre-malignant condition known as monoclonal gammopathy of undetermined significance (MGUS) can be present for many years prior to development of overt disease.[1]
There is strong evidence to suggest that bone marrow mesenchymal stem cell (BMMSC) from patients with MM show a transformed phenotype: supporting malignant plasma cell survival, proliferation, and evasion of chemotherapymediated cell death.[7,8,9,10,11]
The BMMSC phenotype in MGUS patients is less-well characterised.[7]
Summary
One characteristic feature of MM is that a pre-malignant condition known as monoclonal gammopathy of undetermined significance (MGUS) can be present for many years prior to development of overt disease.[1] No specific genetic alterations have yet been identified that distinguish patients with MGUS from those with MM, suggesting that another factor, such as transformation of the microenvironment are likely drivers of progression.[2,3] Malignant plasma cells have an absolute requirement for localisation within the bone marrow niche, which leads to a characteristic feature of MM: the relative rarity of disease metastasis to sites outside the marrow microenvironment This suggests that, in common with most malignancies, stromal support of cancer cell survival in MM is important for maintaining and even driving disease.[4,5,6]. The phenotypic changes resulting from this altered transcriptome appear to permit increased stromal support of the malignant plasma cell, and decreased osteoblastic differentiated function (bone mineralisation).[7,8,9,10,11] The former is through both physical (that is, cell–cell) interactions, and secretion of a number of paracrine factors that support malignant plasma cell survival, proliferation, migration and chemoresistance.[5,6,13] a number of signalling pathways have been implicated in the differentiation of BMMSCs there remains a lack of clarity as to their role
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