Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma
Autoři:
Pilar Delgado aff001; Ángel F. Álvarez-Prado aff001; Ester Marina-Zárate aff001; Isora V. Sernandez aff001; Sonia M. Mur aff001; Jorge de la Barrera aff002; Fátima Sanchez-Cabo aff002; Marta Cañamero aff003; Antonio de Molina aff004; Laura Belver aff001; Virginia G. de Yébenes aff001; Almudena R. Ramiro aff001
Působiště autorů:
B Lymphocyte Biology Lab. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff001; Bioinformatics Unit. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff002; Roche Pharma, Penzberg, Germany
aff003; Comparative Medicine Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff004
Vyšlo v časopise:
Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma. PLoS Genet 16(12): e1008960. doi:10.1371/journal.pgen.1008960
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008960
Souhrn
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.
Klíčová slova:
Carcinogenesis – B cells – Cancers and neoplasms – Malignant tumors – Mammalian genomics – Mouse models – Spleen
Zdroje
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