PT  - JOURNAL ARTICLE
AU  - Pilar Delgado
AU  - Ángel F Álvarez-Prado
AU  - Ester Marina-Zárate
AU  - Isora V Sernandez
AU  - Sonia M Mur
AU  - Jorge de la Barrera
AU  - Fátima Sanchez-Cabo
AU  - Marta Cañamero
AU  - Antonio de Molina
AU  - Laura Belver
AU  - Virginia G de Yebenes
AU  - Almudena R Ramiro
TI  - Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma
AID  - 10.1101/2020.06.29.177303
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.29.177303
4099  - http://biorxiv.org/content/early/2020/06/29/2020.06.29.177303.short
4100  - http://biorxiv.org/content/early/2020/06/29/2020.06.29.177303.full
AB  - Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GCs B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their immunoglobulin (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 supraactivity 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.