AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway

Activation-induced deaminase (AID) initiates secondary antibody diversification in germinal center B cells, giving rise to higher affinity antibodies through somatic hypermutation (SHM) or to isotype-switched antibodies through class switch recombination (CSR). SHM and CSR are triggered by AID-mediated deamination of cytosines in immunoglobulin genes. Importantly, AID activity in B cells is not restricted to Ig loci and can promote mutations and pro-lymphomagenic translocations, establishing a direct oncogenic mechanism for germinal center-derived neoplasias. AID is also expressed in response to inflammatory cues in epithelial cells, raising the possibility that AID mutagenic activity might drive carcinoma development. We directly tested this hypothesis by generating conditional knock-in mouse models for AID overexpression in colon and pancreas epithelium. AID overexpression alone was not sufficient to promote epithelial cell neoplasia in these tissues, in spite of displaying mutagenic and genotoxic activity. Instead, we found that heterologous AID expression in pancreas promotes the expression of NKG2D ligands, the recruitment of CD8(+) T cells, and the induction of epithelial cell death. Our results indicate that AID oncogenic potential in epithelial cells can be neutralized by immunosurveillance protective mechanisms.AP‐G is a fellow of the research training program (FPU‐ AP2009‐1732) funded by the Ministerio de Educación, Cultura y Deporte, PP‐D was an FPI fellow from the Ministerio de Ciencia e Innovación. ARR is supported by Centro Nacional de Investigaciones Cardiovaculares (CNIC). This work was funded by grants from the Ministerio de Economía y Competitividad (SAF2010‐21394, SAF2013‐42767‐R) and the European Research Council Starting Grant program (BCLYM‐207844) to ARR. The CNIC is supported by the Ministerio de Economía y Competitividad and the Pro‐CNIC Foundation. FXR is supported by SAF2011‐29530 and ONCOBIO Consolider grants from Ministerio de Economía y Competitividad (Madrid, Spain), RTICC from Instituto de Salud Carlos III, and grant 256974 from European Union Seventh Framework Programme to FXR

AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway

Activation-induced deaminase (AID) initiates secondary antibody diversification in germinal center B cells, giving rise to higher affinity antibodies through somatic hypermutation (SHM) or to isotype-switched antibodies through class switch recombination (CSR). SHM and CSR are triggered by AID-mediated deamination of cytosines in immunoglobulin genes. Importantly, AID activity in B cells is not restricted to Ig loci and can promote mutations and pro-lymphomagenic translocations, establishing a direct oncogenic mechanism for germinal center-derived neoplasias. AID is also expressed in response to inflammatory cues in epithelial cells, raising the possibility that AID mutagenic activity might drive carcinoma development. We directly tested this hypothesis by generating conditional knock-in mouse models for AID overexpression in colon and pancreas epithelium. AID overexpression alone was not sufficient to promote epithelial cell neoplasia in these tissues, in spite of displaying mutagenic and genotoxic activity. Instead, we found that heterologous AID expression in pancreas promotes the expression of NKG2D ligands, the recruitment of CD8(+) T cells, and the induction of epithelial cell death. Our results indicate that AID oncogenic potential in epithelial cells can be neutralized by immunosurveillance protective mechanisms.AP‐G is a fellow of the research training program (FPU‐ AP2009‐1732) funded by the Ministerio de Educación, Cultura y Deporte, PP‐D was an FPI fellow from the Ministerio de Ciencia e Innovación. ARR is supported by Centro Nacional de Investigaciones Cardiovaculares (CNIC). This work was funded by grants from the Ministerio de Economía y Competitividad (SAF2010‐21394, SAF2013‐42767‐R) and the European Research Council Starting Grant program (BCLYM‐207844) to ARR. The CNIC is supported by the Ministerio de Economía y Competitividad and the Pro‐CNIC Foundation. FXR is supported by SAF2011‐29530 and ONCOBIO Consolider grants from Ministerio de Economía y Competitividad (Madrid, Spain), RTICC from Instituto de Salud Carlos III, and grant 256974 from European Union Seventh Framework Programme to FXR

Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

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