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Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma
McNee, G Eales, KL Wei, W Williams, DS Barkhuizen, A Bartlett, DB Essex, S Anandram, S Filer, A Moss, PAH
McNee, G
Eales, KL
Wei, W
Williams, DS
Barkhuizen, A
Bartlett, DB
Essex, S
Anandram, S
Filer, A
Moss, PAH
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2016-07-11
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Abstract
© 2017 Macmillan Publishers Limited, part of Springer Nature. 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.
Citation
McNee, G., Eales, K. L., Wei, W., Williams, D. S. et al. (2017) Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma, Leukemia, 31, pp. 373–381. DOI: 10.1038/leu.2016.187
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PubMed ID
27400413 (pubmed)
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Journal article
Language
en
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© 2016The Authors. Published by Springer Nature. This is an open access article available under a Creative Commons licence.
The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/leu.2016.187
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ISSN
0887-6924
EISSN
1476-5551
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Sponsors
GMcN and DSW were supported by Bloodwise grant number 13039, SE and DBB by Cancer Research UK grant C1520/A9992 and KLE through Doctoral Training Grant from the Medical Research Council, reference MR/K501323/1.
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Licence for published version: Creative Commons Attribution 4.0 International