IgM and IgG1 B cell receptors differentially affect B cell fates and dictate the pathogenesis of mature B cell lymphomas
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.
Authors
- Roberto Chiarle (ORCID: https://orcid.org/0000-0003-1564-8531)
- Ashima Shukla (ORCID: https://orcid.org/0000-0001-6943-5270)
- Ari Waisman (ORCID: https://orcid.org/0000-0003-4304-8234)
- Ajay Abraham (ORCID: https://orcid.org/0000-0003-4094-2476)
- Robert C. Rickert (ORCID: https://orcid.org/0000-0003-4292-1708)
- Taek-Chin Cheong (ORCID: https://orcid.org/0000-0002-0939-9412)
- Daniel Balsells (ORCID: https://orcid.org/0000-0002-6978-1883)
- Prathyaya Ramesh (ORCID: https://orcid.org/0000-0001-9776-598X)
- Daniela Samaniego‐Castruita (ORCID: https://orcid.org/0000-0001-6082-6603)
- Rebecca Schmitz (ORCID: https://orcid.org/0000-0001-5266-697X)
- Rebecca Southern (ORCID: https://orcid.org/0000-0002-1354-4635)
- Isabella Han
- Vipul Shukla (ORCID: https://orcid.org/0000-0003-1422-5182)
- Carlos Montes
- Mi Thao Tran
Institutions
- Northwestern University (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Johannes Gutenberg University Mainz (DE)
- Discovery Institute (US)
- University Medical Center (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Institute of Molecular Biology (DE)
- University of Turin (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1126/sciadv.adp9391
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00