Targeting 3D chromosomal architecture at the RANK loci to suppress myeloma-driven osteoclastogenesis

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
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
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190249Inhibition of osteoclastogenesis by immunomodulatory complexesCarl GoodyearMedical Research Scotland (MEDRESSC)349 FRGIII - Immunology
168076Targeting bone disease in myelomaCarl GoodyearWorldwide Cancer Research (WWCANRES)13-1215III - Immunology
165276The simultaneous targeting of inflammatory and osteoglastogenic mechanisms in rheumatoid arthritisCarl GoodyearVersus Arthritis (ARTRESUK)MP/19701III - Immunology