TY - JOUR
T1 - Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma
AU - Delgado, Pilar
AU - Álvarez-Prado, Ángel F.
AU - Marina-Zárate, Ester
AU - Sernandez, Isora V.
AU - Mur, Sonia M.
AU - de la Barrera, Jorge
AU - Sanchez-Cabo, Fátima
AU - Cañamero, Marta
AU - de Molina, Antonio
AU - Belver, Laura
AU - de Yébenes, Virginia G.
AU - Ramiro, Almudena R.
N1 - Publisher Copyright:
© 2020 Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/12/23
Y1 - 2020/12/23
N2 - 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 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 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.
AB - 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 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85098941874&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1008960
DO - 10.1371/journal.pgen.1008960
M3 - Article
C2 - 33362210
AN - SCOPUS:85098941874
SN - 1553-7390
VL - 16
JO - PLoS Genetics
JF - PLoS Genetics
IS - 12 December
M1 - e1008960
ER -