Antigen-mediated regulation in monoclonal gammopathies and myeloma
Shiny Nair, … , Eric Meffre, Madhav V. Dhodapkar
Shiny Nair, … , Eric Meffre, Madhav V. Dhodapkar
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e98259. https://doi.org/10.1172/jci.insight.98259.
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Research Article Oncology

Antigen-mediated regulation in monoclonal gammopathies and myeloma

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.

Authors

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, Leif Bergsagel, Dirk Hose, Richard A. Flavell, Pramod K. Mistry, Eric Meffre, Madhav V. Dhodapkar

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Figure 5

Reactivity of clonal plasma cells and Ig to lipid antigen in vivo.

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Reactivity of clonal plasma cells and Ig to lipid antigen in vivo. (A) S...
(A) Serum protein electrophoresis (SPEP) was performed on serum specimens obtained from tumor-engrafted MIS(KI)TRG6 mice injected with either PBS or GlcSph. Fractions shown are α-1 and -2 globulin, β globulin, and γ globulin. The arrow indicates the paraprotein (top panel). The bottom panel shows densitometry quantitation of paraprotein seen in PBS- vs. GlcSph-injected mice performed using ImageJ software (n = 5) (*P < 0.05,Welch’s t test). (B) Representative contour plots show the percentage of human CD38+CD138+ plasma cells and tumor light-chain profile among human cellular compartment (mCD45−mTer119−) in BM mononuclear cells obtained from tumor-engrafted (IgGκ) mice after 3 weeks of injections with PBS or GlcSph (the gating strategy shown in Supplemental Figure 7). The dot plot shows the fold increase in CD38+CD138+ plasma cells in BM of engrafted mice after injection of GlcSph over those injected with PBS (n = 3). (C)The dot plot shows the levels of human light-chain–restricted antibodies (μg/ml) in mouse sera, detected by ELISA. Data represent mean ± SEM (n = 3). (D) Heatmap for the expression of CD33, CD56, CD38, and CD138 on clonal κ and nonclonal λ plasma cells in GlcSph-injected tumor engrafted mice as in B, as analyzed by mass cytometry (CyTOF). Bars represent expression scales.