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

Katja Thümmler, Mark T.S. Williams, Susan Kitson, Shatakshi Sood, Moeed Akbar, John J. Cole, Ewan Hunter , Richard Soutard , Carl S. Goodyear*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Article number2104070
Number of pages10
JournalOncoImmunology
Volume11
Issue number1
Early online date1 Aug 2022
DOIs
Publication statusE-pub ahead of print - 1 Aug 2022

Keywords

  • FcγR, epigenetic, RANK, multiple myeloma, osteoclasts
  • receptors, IgG/genetics
  • multiple myeloma/genetics
  • osteoclasts/metabolism
  • humans
  • tumor microenvironment
  • cell differentiation/genetics
  • osteogenesis/genetics

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