학술논문
BTG1 mutation yields supercompetitive B cells primed for malignant transformation.
Document Type
article
Author
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; Geng, Huimin
Source
Science. 379(6629)
Subject
Language
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.