Antigen-mediated regulation in monoclonal gammopathies and myeloma

Autor: Pramod K. Mistry, Dirk Hose, Madhav V. Dhodapkar, Lin Zhang, Chandra Sekhar Boddupalli, Mariateresa Fulciniti, Richard A. Flavell, Joel Sng, Navin Rauniyar, Marta Chesi, Terri L. Parker, Eric Meffre, Leif Bergsagel, Bart Barlogie, Rachael Sexton, Natalia Neparidze, Nikhil C. Munshi, Robert Z. Orlowski, Shiny Nair, Michael A. Lopez, Anja Seckinger
Přispěvatelé: Hematology, Basic (bio-) Medical Sciences
Rok vydání: 2017
Předmět:
0301 basic medicine
Epidemiology
B-cell receptor
Plasma Cells
Paraproteinemias
Multiple Myeloma/genetics
Monoclonal Gammopathy of Undetermined Significance
03 medical and health sciences
Mice
Antigen
Sequence Analysis
Protein
Gammopathy
medicine
Animals
Humans
Cytogenetic Analysis/methods
Clonal Selection
Antigen-Mediated
Multiple myeloma
Paraproteinemias/genetics
biology
hematology
Gene Expression Profiling
General Medicine
Sequence Analysis
Protein/methods
medicine.disease
Molecular biology
030104 developmental biology
Plasma Cells/immunology
Polyclonal antibodies
Monoclonal
Cytogenetic Analysis
Monoclonal Gammopathy of Undetermined Significance/genetics
biology.protein
Female
Gene Expression Profiling/methods
Clone (B-cell biology)
Multiple Myeloma
Clonal Selection
Antigen-Mediated/genetics
Monoclonal gammopathy of undetermined significance
Research Article
Zdroj: JCI insight. 3(8)
ISSN: 2379-3708
Popis: 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.
Databáze: OpenAIRE
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