Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/13248
Título
Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.
Autor(es)
Delgado, Pilar CNIC | Alvarez-Prado, Angel Francisco CNIC | Marina-Zarate, Ester CNIC | Sernandez, Isora V. | Mur, Sonia M. CNIC | de la Barrera, Jorge CNIC | Sanchez-Cabo, Fatima CNIC | Cañamero, Marta | Molina-Iracheta, Antonio CNIC | Belver, Laura | de Yebenes, Virginia G CNIC | Ramiro, Almudena R CNIC
Fecha de publicación
2020-12
Cita
PLoS Genet. 2020; 16(12):e1008960
Idioma
Inglés
Tipo de documento
journal article
Resumen
Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supra-activity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.
MESH
Genetic Heterogeneity | Animals | Cell Transformation, Neoplastic | Cells, Cultured | Clonal Evolution | Cytidine Deaminase | Female | Lymphoma, B-Cell | Male | Mice | Mice, Inbred C57BL | Mutation | Uracil-DNA Glycosidase
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