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Cited by 60Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and Treatment

Antigen-mediated regulation in monoclonal gammopathies and myeloma

Open access
Nair, Shiny, Sng, Joel, Boddupalli, Chandra Sekhar, Seckinger, Anja, Chesi, Marta, Fulciniti, Mariateresa, Zhang, Lin, Rauniyar, Navin +13 more·2018·JCI Insight
DOI 10.1172/jci.insight.98259PMC PMC5931125
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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.

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  • Patients exposed to certain agents (Agent Orange, pesticides, 9/11 World Trade Center dust) or suffering from specific conditions (HIV or Gaucher) have a higher prevalence of clonal populations.

    “Importantly, it has also been demonstrated that patients exposed to certain agents (e.g. Agent Orange in Vietnam veterans, pesticides in agricultural worker, or 9/11 World Trade Center dust in first responders) or those suffering from specific conditions (such as HIV or Gaucher) have a higher prevalence of these clonal populations. 37-39 40,41 42”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [41]

    The Introduction (page unavailable) states that myeloma risk is markedly increased in patients with Gaucher disease, supporting the Gaucher portion of the claim. Our copy does not report higher prevalence of clonal populations after Agent Orange, pesticide, or World Trade Center dust exposure, or in people with HIV; nor does it directly compare the prevalence of clonal populations in Gaucher disease. (LLM, conf=0.82)

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  • In Gaucher disease, chronic stimulation of B-cells against lyso-glucosylceramide (LGL1) promotes the development of MGUS with clonal immunoglobulin specific for LGL1.

    “This idea of chronic stimulation or B-cells re-entering has found robust evidence in the Gaucher disease where the chronic stimulation of B-cells against lyso-glucosylceramide (LGL1) promotes the development of MGUS with clonal immunoglobulin specific for LGL1.40,41”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [41]

    The clonal-Ig results report that immunoglobulins from Gaucher disease–associated gammopathy bind glucosylsphingosine. The Discussion (page unavailable) says persistent stimulation by this accumulated lipid could contribute to gammopathy, but it does not establish that such stimulation causes MGUS to develop; its in vivo experiment measured growth of an existing clone. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The B-cells from which multiple myeloma originates experience prolonged or chronic stimulation in the germinal center.

    “In fact, several studies have supported the idea that the B-cells from which MM originate, experience a prolonged/chronic stimulation in the GC.15,40,41,70,71”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [41]

    The Discussion (page unavailable) proposes that chronic immune activation by lipid antigens may contribute to the expansion and transformation of B/plasma cells in a subset of myeloma patients. It does not establish that the precursor B cells experienced prolonged stimulation in the germinal center, or extend that model to MM generally. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cites

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Authors
Nair, S., Sng, J., Boddupalli, C. S., Seckinger, A., Chesi, M., Fulciniti, M., Zhang, L., Rauniyar, N., Lopez, M., Neparidze, N., Parker, T., Munshi, N. C., Sexton, R., Barlogie, B., Orlowski, R., Bergsagel, L., Hose, D., Flavell, R. A., Mistry, P. K., Meffre, E., & Dhodapkar, M. V.
Affiliations
  • Department of Medicine and
  • Yale University (US)
  • University Hospital Heidelberg (DE)
  • Mayo Clinic in Arizona (US)
  • Dana-Farber Cancer Institute (US)
  • Cancer Research And Biostatistics (US)
  • Mount Sinai Medical Center, New York, New York, USA.
  • The University of Texas MD Anderson Cancer Center (US)
  • Mayo Clinic, Scottsdale, Arizonia, USA.
Corresponding author
Dhodapkar, Madhav V.
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2018-04-19
Volume
3
Issue
8
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.98259
PMC
PMC5931125
OpenAlex
W2800589896
Cited by
60
References
2
Citations by year
2026: 2 · 2025: 8 · 2024: 4 · 2023: 9 · 2022: 9 · 2021: 5 · 2020: 17 · 2019: 5 · 2018: 1
FWCI
5.02
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • NIH (CA197603)
  • Leukemia and Lymphoma Society (Translational Research Program)
  • MMRF (Perelman Family Fonudation Fund)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
monoclonal gammopathy of undetermined significance, multiple myeloma, Gaucher disease, B cell clones, plasma cells, carcinogenesis, gene expression profiling
MeSH terms
Animals, Female, Humans, Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, Paraproteinemias, Plasma Cells, Sequence Analysis, Protein, Cytogenetic Analysis, Gene Expression Profiling, Mice, Clonal Selection, Antigen-Mediated

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