1. BTG1 mutation yields supercompetitive B cells primed for malignant transformation.
- Author
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Mlynarczyk, Coraline, Teater, Matt, Pae, Juhee, Chin, Christopher, Wang, Ling, Arulraj, Theinmozhi, Barisic, Darko, Papin, Antonin, Hoehn, Kenneth, Kots, Ekaterina, Ersching, Jonatan, Bandyopadhyay, Arnab, Barin, Ersilia, Poh, Hui, Evans, Chiara, Chadburn, Amy, Chen, Zhengming, Shen, Hao, Isles, Hannah, Pelzer, Benedikt, Tsialta, Ioanna, Doane, Ashley, Rehman, Muhammad, Melnick, Jonah, Morgan, Wyatt, Nguyen, Diu, Elemento, Olivier, Kharas, Michael, Jaffrey, Samie, Scott, David, Khelashvili, George, Meyer-Hermann, Michael, Victora, Gabriel, Melnick, Ari, and Geng, Huimin
- Subjects
Animals ,Humans ,Mice ,Antibody Affinity ,B-Lymphocytes ,Germinal Center ,Mutation ,Neoplasm Proteins ,Lymphoma ,Large B-Cell ,Diffuse ,Cell Transformation ,Neoplastic ,Selection ,Genetic - Abstract
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
- Published
- 2023