IgM and IgG1 B cell receptors differentially affect B cell fates and dictate the pathogenesis of mature B cell lymphomas
Year: 2025
Type: article
Abstract: Malignant B cells rely on B cell receptor (BCR) signals for their survival and growth. Besides the Immunoglobulin M (IgM) BCR, lymphoma cells can also express non-IgM (IgG) BCRs; however, the role of IgG BCRs in malignant B cell is not well understood. Here, we report poorer disease outcomes in diffuse large B cell lymphoma (DLBCL) expressing high IgM versus those expressing IgG1. Using isogenic lymphoma cells expressing distinct BCRs, we found that IgM expressing cells strongly outcompete their IgG1 counterparts. Mechanistically, IgG1 BCR is associated with a dysfunctional mitochondrial state and reduced cell survival. We show that mitochondrial dysfunction is triggered by accentuated calcium responses downstream of IgG1 BCR. Genetic reversal of IgG1 to IgM, pharmacological dampening of calcium signaling, or treatment with interleukin-21 can correct mitochondrial defects and rescue IgG1 survival. Our findings demonstrate that distinct BCR isotypes are inherently unique and can differentially affect B cell lymphoma pathogenesis.
Source: Science Advances
Institutions: Northwestern University, Sanford Burnham Prebys Medical Discovery Institute, Boston Children's Hospital, Harvard University, University of Turin, European Institute of Oncology, University Medical Center of the Johannes Gutenberg University Mainz, Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4413817771