Thümmler, K. , Williams, M. T.S., Kitson, S., Sood, S., Akbar, M., Cole, J. J., Goodyear, C. S. , Hunter, E. and Soutar, R. (2022) Targeting 3D chromosomal architecture at the RANK loci to suppress myeloma-driven osteoclastogenesis. OncoImmunology, 11(1), 2104070. (doi: 10.1080/2162402X.2022.2104070) (PMID:35936985) (PMCID:PMC9348127)
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Abstract
Bone disease represents a major cause of morbidity and mortality in Multiple Myeloma (MM); primarily driven by osteoclasts whose differentiation is dependent on expression of RANKL by MM cells. Notably, costimulation by ITAM containing receptors (i.e., FcγR) can also play a crucial role in osteoclast differentiation. Modeling the pathology of the bone marrow microenvironment with an ex vivo culture system of primary human multiple myeloma cells, we herein demonstrate that FcγR-mediated signaling, via staphylococcal protein A (SpA) IgG immune-complexes, can act as a critical negative regulator of MM-driven osteoclast differentiation. Interrogation of the mode-of-action revealed that FcγR-mediated signaling causes epigenetic modulation of chromosomal 3D architecture at the RANK promoter; with altered spatial orientation of a proximal super enhancer. Combined this leads to substantial down-regulation of RANK at a transcript, protein, and functional level. These observations shed light on a novel mechanism regulating RANK expression and provide a rationale for targeting FcγR-signaling for the amelioration of osteolytic bone pathology in disease.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Muecklisch, Dr Katja and Akbar, Mr Moeed and Sood, Dr Shatakshi and Kitson, Miss Susan and Cole, Mr John and Williams, Dr Mark and Soutar, Dr Richard and Goodyear, Professor Carl |
Creator Roles: | Williams, M.Formal analysis, Investigation, Methodology, Writing – original draft Kitson, S.Investigation, Methodology Sood, S.Investigation Akbar, M.Investigation Cole, J.Formal analysis, Methodology, Software, Writing – review and editing Goodyear, C.Conceptualization, Formal analysis, Funding acquisition, Visualization, Writing – original draft, Writing – review and editing Soutar, R.Resources, Writing – review and editing |
Authors: | Thümmler, K., Williams, M. T.S., Kitson, S., Sood, S., Akbar, M., Cole, J. J., Goodyear, C. S., Hunter, E., and Soutar, R. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
Journal Name: | OncoImmunology |
Publisher: | Taylor & Francis |
ISSN: | 2162-4011 |
ISSN (Online): | 2162-402X |
Published Online: | 01 August 2022 |
Copyright Holders: | Copyright © 2022 The Authors |
First Published: | First published in OncoImmunology 11(1):2104070 |
Publisher Policy: | Reproduced under a Creative Commons License |
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