Abstract 925: A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B

Introduction: Advanced DNA sequencing technologies have revealed a substantial endogenous source of mutations in cancers, the human DNA-mutating enzyme APOBEC3B (A3B). This protein changes DNA cytosines into uracils (C-to-U), which can become “immortalized” in the genome as C-to-T or C-to-G mutations depending on how each uracil lesion is processed. However, mice lack analogous carcinogenic A3 enzymes, which makes a definitive cause-and-effect model of A3-induced carcinogenesis difficult to establish. Results: Using C57BL/6 mice, we have generated a novel genetically engineered mouse model (GEMM) expressing the human protein A3B, where it is driven constitutively from the Rosa26 locus in combination with the strong synthetic CAG promoter. Importantly, tumor-free survival data suggest that CAG A3B mice develop tumors at an increased rate compared to wild-type mice. These CAG A3B mice develop predominantly lymphoid neoplasms including B- and T-cell lymphomas and marked splenomegaly, and less frequently lung and liver cancers. Using immunohistochemical and whole-genome sequencing techniques, we have further characterized the tumors arising in these novel GEMMs. The above analyses thus far have revealed that A3B is actively driving tumor formation, as seen by an enrichment of canonical APOBEC-related mutations in these cancers. Conclusion: Overall, the CAG A3B mice are the first GEMMs demonstrating the potential for A3B to drive tumor formation in vivo, with a predilection towards blood malignancies. They will be an invaluable tool for characterizing A3B-driven mutational processes in an organism and testing novel therapeutic strategies against APOBEC-induced cancer initiation and progression. Citation Format: Cameron C. Durfee, Prokopios P. Argyris, Matthew C. Jarvis, Rena Levin-Klein, Emily K. Law, Reuben S. Harris. A genetically engineered mouse model for carcinogenesis by the human enzyme APOBEC3B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 925.