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Cumulative Antigen Suppression Reduces Clonal Plasma Cell Evolution in Gaucher Disease
Noor Ul Ain1, Noffar Bar1, Lilu Guo2
1Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
American Journal of Hematology
|June 17, 2026
Summary
Gaucher disease patients have a ninefold higher risk of developing monoclonal gammopathy. Therapy for Gaucher disease significantly reduces this risk, demonstrating antigen-driven oncogenesis is modifiable.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Chronic antigenic stimulation is linked to monoclonal gammopathy and multiple myeloma pathogenesis.
- Longitudinal human data on antigen exposure and clonal plasma cell evolution are limited.
- Gaucher disease (GD) involves glucosylsphingosine (LysoGL1) accumulation, a direct antigen target.
Purpose of the Study:
- To investigate the association between Gaucher disease and monoclonal gammopathy development.
- To determine if GD-specific therapy modifies the risk of monoclonal gammopathy.
- To establish GD as a model for antigen-driven oncogenesis.
Main Methods:
- Longitudinal retrospective cohort study of 235 adults with Gaucher disease.
- Incident-only ascertainment from a gammopathy-free baseline.
- Analysis of monoclonal gammopathy incidence, risk factors (sex), and therapy effects on risk and LysoGL1 levels.
Main Results:
- 31 patients (13.2%) developed monoclonal gammopathy, a ninefold excess risk (SIR 9.04).
- Male sex independently increased risk (HR 3.30).
- GD-specific therapy showed a dose-dependent risk reduction (HR 0.91 per year), extending MGUS-free time by 8.4 years; therapy suppressed LysoGL1.
Conclusions:
- Gaucher disease significantly increases monoclonal gammopathy risk, highlighting antigen-driven oncogenesis.
- Therapeutic reduction of the antigenic stimulus (LysoGL1) modifies oncogenic trajectory.
- GD serves as a model for investigating antigen-driven oncogenesis and potential therapeutic interventions in chronic inflammatory states.
