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Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma
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Summ a r yAntigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies.Patients with Gaucher's disease have an increased risk of monoclonal gammopathies.Here we show that the clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy is reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice.Clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC).Substrate reduction ameliorates Gaucher's disease-associated gammopathy in mice.Thus, longterm immune activation by lysolipids may underlie both Gaucher's disease-associated gammopathies and some sporadic monoclonal gammopathies.M ultiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) are characterized by clonal expansion of transformed plasma cells. 1 Analyses of immunoglobulin genes in tumor cells have provided evidence of antigen-driven selection, with restricted heavy-chain variableregion use and highly hypermutated immunoglobulin heavy-and light-chain genes. [2][3]][4][5][6] However, the antigens underlying the origins of most MGUS and myeloma clones remain unknown.Hyperphosphorylated modification of stomatin (EPB72)-like 2 protein (STOML2, which is identical to paratarg-7) due to the inactivation of protein phosphatase 2A was identified as a target of certain paraproteins and an inherited risk factor for the development of gammopathies.[7][8][9] A recent study identified sumoylated heat-shock protein 90 as another inherited risk factor for plasma-cell dyscrasia.10 However, there remains a need to identify the antigenic origins of MGUS and myeloma that may be amenable to targeted prevention.Lipids (such as pristane) were implicated in the earliest models of murine plasmacytoma, 11 and lipid disorders such as Gaucher's disease and obesity are associated with an increased risk of myeloma.12,13 The risk of myeloma is markedly higher among patients with Gaucher's disease, in whom myeloma is now emerging as a leading cause of cancer-related death, than in the general population.13 Glucocerebrosidase deficiency in Gaucher's disease leads to increases in the level of LGL1.14 Recently, we identified a subset of human and murine LGL1-specific CD1d-restricted type 2 natural killer T cells that constitutively expressed markers of follicular helper T cells and helped in the differentiation of lipid-reactive plasma cells.15 In an earlier study, we found an elevation of type 2 natural killer T cells against another bioactive lysolipid, LPC, in myeloma.16 These studies led us to test whether the clonal immunoglobulin in Gaucher's disease-associated myeloma and sporadic myeloma was reactive against LGL1 and LPC. Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma
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“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 [40]
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“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 [40]
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“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 [40]
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Metadata
- Authors
- Nair, S., Branagan, A. R., Liu, J., Boddupalli, C. S., Mistry, P. K., & Dhodapkar, M. V.
- Affiliations
- Yale Cancer Center (US)
- Yale University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-02-11
- Volume
- 374
- Issue
- 6
- Pages
- 555-561
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4804194
- OpenAlex
- W2321709204
- Cited by
- 203
- References
- 26
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 11 · 2023: 22 · 2022: 27 · 2021: 17 · 2020: 26 · 2019: 22 · 2018: 23 · 2017: 17 · 2016: 14
- FWCI
- 24.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (NIAMS 65932)
- National Cancer Institute (R01CA135110, CA 106802, CA135110, R01CA156689, CA156689, R01CA106802, R35CA197603, P30CA016359)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034989)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR065932)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- multiple myeloma, Gaucher disease, lysolipids, lysophosphatidylcholine, antigen-driven selection, substrate reduction therapy, lipid metabolism, monoclonal gammopathy of undetermined significance, plasma cell dyscrasia
- MeSH terms
- Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gaucher Disease, Glucosylceramides, Humans, Immunoglobulins, Lysophosphatidylcholines, Multiple Myeloma, Paraproteinemias, Mice
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