Multiple myeloma (MM) is an incurable malignant disease of plasma cells, representing the most severe form of paraproteinaemia. In most cases it arises from a clinically benign state, termed monoclonal gammopathy of undetermined significance (MGUS), a common condition in the elderly.
Both normal and malignant plasma cells need to be localized within the bone marrow niche in order to survive and proliferate. From studies of MM, we now understand that much of this requirement is due to interactions between the malignant plasma cells and other cell types in the bone marrow; however, the precise nature of these interactions is not clear.
We currently know little about the nature of the bone marrow microenvironment in MGUS – knowledge that is key to understanding how we could treat this important patient group. As MM is effectively incurable, identifying and treating those patients with MGUS, who are at risk of progressing, represents an attractive means of greatly improving survival.
In a recent publication in the journal Leukemia, we focused on the role of the bone marrow mesenchymal stem cell (BMMSC) in the development of MGUS and MM. This cell type appears to be a particularly important component of the bone marrow microenvironment, as it has been shown to be critical in supporting malignant plasma cell survival, proliferation and resistance to therapy.
Through transcriptional profiling, we identified a new role for peptidyl arginine deiminase 2 (PADI2) in the development of MGUS and MM. This enzyme, which is upregulated in the BMMSCs of patients with MGUS and MM, catalyzes a post-translational modification, (deimination of arginine) resulting in the creation of a peptidyl citrulline residue.
The major finding that we made was the identification of PADI2-mediated deimination of arginine residue 26 of histone H3 (H3 R26), a process known as citrullination. We found that in BMMSCs, from both MGUS and MM patients, we could detect significant levels of citrullinated histone H3 R26, which results in the upregulation of a key cytokine, IL-6.
Given the previous findings that IL-6 expression by BMMSCs altered plasma cell response to the proteasomal inhibitor bortezomib, we investigated the effect of BMMSC PADI2 activity on plasma cell response to this drug in co-culture. We found that increasing PADI2 expression also increased the resistance of a plasma cell line to bortezomib. Importantly, as increased PADI2 was noted in BMMSCs from MGUS patients, this appears to be a very early drug resistance mechanism.
Studies over a number of years have shown the importance of BMMSCs in providing pro-malignant signalling through multiple pathways – in particular, the IL-6/IL-6 receptor interaction, stromal cell-derived factor 1/CXCR4 interaction and that of scatter factor/cMET. Intriguingly, we found that PADI2 appeared to be able to control the expression of the BMMSC-expressed partner of each of these signalling axes, a result that is particularly important, given the disappointing results from a recent trial testing the efficacy of anti-IL-6 therapy (siltuximab).
The IL-6 promoter is almost certainly one of a large number in the BMMSC genome, as PADI2 has been shown to have additional targets in other disease settings, suggesting that the effect of increased PADI2 on BMMSC phenotype may be diverse. This urgently needs more work to identify the full effect of PADI2-mediated citrullination of histone H3 R26.
The PADI enzymes, especially PADI4 have been implicated in a number of chronic inflammatory diseases, including rheumatoid arthritis. Through studies in pre-clinical inflammatory disease models, PADI inhibitors have been shown as surprisingly non-toxic, and as such it would be very interesting to test them in models of MM.
A further interesting aspect of this group of enzymes is the nature of the post-translational modification – the removal of the imino group is physiologically irreversible without protein turnover, and therefore this modification is very long-lasting. This suggests that strategies to inhibit PADI2 therapeutically may have to be used long-term in order to produce significant biological effect.
In summary, our paper has provided an important insight into how the BM microenvironment is transformed in patients with MGUS and how this transformation is maintained in MM. What drives the upregulation of PADI2 is unclear, however, we feel that its identification is critical as it may well represent one of the earliest events in the transformation of the normal BM into one capable of supporting the development of MM.
Dr Daniel Tennant is Principal Investigator in the Institute of Metabolism and Systems Research at the University of Birmingham. Research in his group is concerned with identifying components of the tumor microenvironment that perturb tumor metabolism, with particular emphasis on hypoxia-mediated metabolic transformation. Dan completed his post-doctoral fellowship in 2011 at the CR-UK Beatson Institute for Cancer Research at the University of Glasgow with Professor Eyal Gottlieb and obtained his PhD at the University of Manchester. (@tennantlab)
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