Title | mutation yields supercompetitive B cells primed for malignant transformation. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | 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 HXian, Evans CM, Chadburn A, Chen Z, Shen H, Isles HM, Pelzer B, Tsialta I, Doane AS, Geng H, Rehman MHassan, Melnick J, Morgan W, Nguyen DTT, Elemento O, Kharas MG, Jaffrey SR, Scott DW, Khelashvili G, Meyer-Hermann M, Victora GD, Melnick A |
Journal | Science |
Volume | 379 |
Issue | 6629 |
Pagination | eabj7412 |
Date Published | 2023 Jan 20 |
ISSN | 1095-9203 |
Keywords | Animals, Antibody Affinity, B-Lymphocytes, Cell Transformation, Neoplastic, Germinal Center, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Mutation, Neoplasm Proteins, Selection, Genetic |
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 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. |
DOI | 10.1126/science.abj7412 |
Alternate Journal | Science |
PubMed ID | 36656933 |