Antigen-mediated regulation in monoclonal gammopathies and myeloma

Shiny Nair, Joel Sng, Chandra Sekhar Boddupalli, Anja Seckinger, Marta Chesi, Mariateresa Fulciniti, Lin Zhang, Navin Rauniyar, Michael Lopez, Natalia Neparidze, Terri Parker, Nikhil C. Munshi, Rachael Sexton, Bart Barlogie, Robert Orlowski, Peter Leif Bergsagel, Dirk Hose, Richard A. Flavell, Pramod K. Mistry, Eric Meffre & 1 others Madhav V. Dhodapkar

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number8
DOIs
StatePublished - Apr 19 2018

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Paraproteinemias
Antigens
Gaucher Disease
Plasma Cells
Multiple Myeloma
Lipids
Neoplasms
Monoclonal Gammopathy of Undetermined Significance
Cytogenetic Analysis
Protein Sequence Analysis
Gene Expression Profiling
Liposomes
B-Lymphocytes
Clone Cells
Genome
Growth

Keywords

  • Antigen
  • Cancer
  • Oncology

Cite this

Nair, S., Sng, J., Boddupalli, C. S., Seckinger, A., Chesi, M., Fulciniti, M., ... Dhodapkar, M. V. (2018). Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI insight, 3(8). https://doi.org/10.1172/jci.insight.98259

Antigen-mediated regulation in monoclonal gammopathies and myeloma. / Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar; Seckinger, Anja; Chesi, Marta; Fulciniti, Mariateresa; Zhang, Lin; Rauniyar, Navin; Lopez, Michael; Neparidze, Natalia; Parker, Terri; Munshi, Nikhil C.; Sexton, Rachael; Barlogie, Bart; Orlowski, Robert; Bergsagel, Peter Leif; Hose, Dirk; Flavell, Richard A.; Mistry, Pramod K.; Meffre, Eric; Dhodapkar, Madhav V.

In: JCI insight, Vol. 3, No. 8, 19.04.2018.

Research output: Contribution to journalArticle

Nair, S, Sng, J, Boddupalli, CS, Seckinger, A, Chesi, M, Fulciniti, M, Zhang, L, Rauniyar, N, Lopez, M, Neparidze, N, Parker, T, Munshi, NC, Sexton, R, Barlogie, B, Orlowski, R, Bergsagel, PL, Hose, D, Flavell, RA, Mistry, PK, Meffre, E & Dhodapkar, MV 2018, 'Antigen-mediated regulation in monoclonal gammopathies and myeloma', JCI insight, vol. 3, no. 8. https://doi.org/10.1172/jci.insight.98259
Nair, Shiny ; Sng, Joel ; Boddupalli, Chandra Sekhar ; Seckinger, Anja ; Chesi, Marta ; Fulciniti, Mariateresa ; Zhang, Lin ; Rauniyar, Navin ; Lopez, Michael ; Neparidze, Natalia ; Parker, Terri ; Munshi, Nikhil C. ; Sexton, Rachael ; Barlogie, Bart ; Orlowski, Robert ; Bergsagel, Peter Leif ; Hose, Dirk ; Flavell, Richard A. ; Mistry, Pramod K. ; Meffre, Eric ; Dhodapkar, Madhav V. / Antigen-mediated regulation in monoclonal gammopathies and myeloma. In: JCI insight. 2018 ; Vol. 3, No. 8.
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