BTG1 mutation yields supercompetitive B cells primed for malignant transformation

• 成果类型: Article
• 署名作者: Mlynarczyk, Coraline; Teater, Matt; Pae, Juhee; Chin, Christopher R.; Wang, Ling; Arulraj, Theinmozhi; Barisic, Darko; Papin, Antonin; Hoehn, Kenneth B.; Kots, Ekaterina; Ersching, Jonatan; Bandyopadhyay, Arnab; Barin, Ersilia; Poh, Hui Xian; Evans, Chiara M.; Chadburn, Amy; Chen, Zhengming; Shen, Hao; Isles, Hannah M.; Pelzer, Benedikt; Tsialta, Ioanna; Doane, Ashley S.; Geng, Huimin; Rehman, Muhammad Hassan; Melnick, Jonah; Morgan, Wyatt; Nguyen, Diu T. T.; Elemento, Olivier; Kharas, Michael G.; Jaffrey, Samie R.; Scott, David W.; Khelashvili, George; Meyer-Hermann, Michael; Victora, Gabriel D.; Melnick, Ari
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Rockefeller University; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Helmholtz Association; Helmholtz-Center for Infection Research; Helmholtz Association; Helmholtz-Center for Infection Research; Cornell University; Weill Cornell Medicine; Yale University; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; University of California System; University of California San Francisco; Qatar Foundation (QF); Weill Cornell Medical College Qatar; University of London; Queen Mary University London; Cornell University; Weill Cornell Medicine; British Columbia Cancer Agency; Braunschweig University of Technology
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11530
• DOI: 10.1126/science.abj7412
• 发表日期: 2023-01-20
• 页码: 252-+
• 关键词: differential expression analysis; germinal center; dynamic regulation; clonal selection; c-myc; protein; immunoglobulin; lymphoma; genes; signatures

摘要

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.