Abstract:
: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 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.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Delgado 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 ARdoi
10.1371/journal.pgen.1008960subject
Has Abstractpub_date
2020-12-23 00:00:00pages
e1008960issue
12eissn
1553-7390issn
1553-7404pii
PGENETICS-D-20-00995journal_volume
16pub_type
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