Delgado, PilarAlvarez-Prado, Angel FranciscoMarina-Zarate, EsterSernandez, Isora V.Mur, Sonia M.de la Barrera, JorgeSanchez-Cabo, FatimaCañamero, MartaMolina-Iracheta, AntonioBelver, Laurade Yebenes, Virginia GRamiro, Almudena R2021-07-192021-07-192020-12PLoS Genet. 2020; 16(12):e10089601553-7404http://hdl.handle.net/20.500.12105/13248Most 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Genetic HeterogeneityAnimalsCell Transformation, NeoplasticCells, CulturedClonal EvolutionCytidine DeaminaseFemaleLymphoma, B-CellMaleMiceMice, Inbred C57BLMutationUracil-DNA GlycosidaseAtribución 4.0 Internacional333622101612e100896010.1371/journal.pgen.1008960PLoS geneticsopen access