Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma

Author:

Delgado PilarORCID,Álvarez-Prado Ángel FORCID,Marina-Zárate Ester,Sernandez Isora V,Mur Sonia M,de la Barrera JorgeORCID,Sanchez-Cabo Fátima,Cañamero Marta,de Molina Antonio,Belver Laura,de Yebenes Virginia G,Ramiro Almudena RORCID

Abstract

ABSTRACTMost 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.

Publisher

Cold Spring Harbor Laboratory

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