BTG1 mutation yields supercompetitive B cells primed for malignant transformation

• Published in: Science (American Association for the Advancement of Science) Vol. 379; no. 6629; p. eabj7412
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 20.01.2023
• Subjects: Acceleration; Adaptive immunity; Animal models; Animals; Antibody Affinity - genetics; Antigens; B-cell lymphoma; B-Lymphocytes - pathology; Cancer; Cell cycle; Cell proliferation; Cell Transformation, Neoplastic - genetics; Clinical outcomes; Clonal selection; Competition; Embryos; Fitness; Fragility; Gene expression; Genes; Genetic transformation; Germinal Center; Health risks; Humans; Immune response; Immune system; Logical Thinking; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Malignancy; Mice; Missense mutation; mRNA; Mutants; Mutation; Myc protein; Natural selection; Neoplasm Proteins - genetics; Pathogenesis; Polyribosomes; Positive selection; Reproductive fitness; S phase; Selection, Genetic; Signal processing; Somatic hypermutation; Target acquisition; Transformations; Translocation; Tumors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abj7412

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 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.