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.
Highlights
Non-Hodgkin-lymphomas (NHL) are high incidence hematological malignancies, with more than 500,000 new cases diagnosed in 2018 worldwide (World Cancer Research Fund, www. wcrf.org)
NHL comprise a number of distinct pathological entities, the vast majority of them arise from the malignant transformation of mature B cells with germinal center (GC) experience
A mouse model to address the contribution of Activation Induced Deaminase (AID) to B cell lymphomagenesis
Summary
Non-Hodgkin-lymphomas (NHL) are high incidence hematological malignancies, with more than 500,000 new cases diagnosed in 2018 worldwide (World Cancer Research Fund, www. wcrf.org). NHL comprise a number of distinct pathological entities, the vast majority of them arise from the malignant transformation of mature B cells with germinal center (GC) experience. Those include follicular lymphoma (FL) and the more aggressive diffuse large B cell lymphoma (DLBCL), which together account for more than 50% of all NHL, as well as Burkitt lymphoma (BL) [1]. T-cell-activated B cells undergo a region-specific recombination reaction called class switch recombination (CSR), which replaces the primary IgM/IgD constant region by alternative downstream constant regions at the Ig heavy (IgH) locus, giving rise to IgG, IgE or IgA isotypes and adding enormous functional versatility to antibody-mediated antigen clearance [4,5,6,7,8]
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