Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.
PLoS Genet
; 16(12): e1008960, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-33362210
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 UG 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfoma de Células B
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Heterogeneidade Genética
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Citidina Desaminase
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Uracila-DNA Glicosidase
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article