Delgado, PilarGarcía-Yébenes Mena, Virginia PilarRamiro, Almudena R.2024-01-092024-01-092020-12-23Delgado P, Álvarez-Prado ÁF, Marina-Zárate E, Sernandez IV, Mur SM, de la Barrera J, Sanchez-Cabo F, Cañamero M, de Molina A, Belver L, de Yébenes VG, Ramiro AR. Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma. PLoS Genet. 2020 Dec 23;16(12):e1008960. doi: 10.1371/journal.pgen.1008960. PMID: 33362210; PMCID: PMC77904091553-740410.1371/journal.pgen.1008960.https://hdl.handle.net/20.500.14352/91978Most 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008960https://pubmed.ncbi.nlm.nih.gov/33362210/open access612.017lymphomaB lymphocyteCiencias24 Ciencias de la Vida