BTG1 mutation yields supercompetitive B cells primed for malignant transformation.
Mlynarczyk C., Teater M., Pae J., Chin CR., Wang L., Arulraj T., Barisic D., Papin A., Hoehn KB., Kots E., Ersching J., Bandyopadhyay A., Barin E., Poh HX., Evans CM., Chadburn A., Chen Z., Shen H., Isles HM., Pelzer B., Tsialta I., Doane AS., Geng H., Rehman MH., Melnick J., Morgan W., Nguyen DTT., Elemento O., Kharas MG., Jaffrey SR., Scott DW., Khelashvili G., Meyer-Hermann M., Victora GD., Melnick A.
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.