<i>BTG1</i> mutation yields supercompetitive B cells primed for malignant transformation
Coraline Mlynarczyk, Matt Teater, Juhee Pae, Christopher R. Chin, Ling Wang, Theinmozhi Arulraj, Darko Barišić, Antonin Papin, Kenneth B. Hoehn, Ekaterina D. Kots, Jonatan Ersching, Arnab Bandyopadhyay, Ersilia Barin, Hui Xian Poh, Chiara M. Evans, Amy Chadburn, Zhengming Chen, Hao Shen, Hannah M. Isles, Benedikt W. Pelzer, Ioanna Tsialta, Ashley S. Doane, Huimin Geng, Muhammad Hassan Rehman, Jonah Melnick, Wyatt Morgan, Diu Nguyen, Olivier Elemento, Michael G. Kharas, Samie R. Jaffrey, David W. Scott, George Khelashvili, Michael Meyer‐Hermann, Gabriel D. Victora, Ari Melnick
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.