Abstract 3445: Germline BRCA2 heterozygosity drives gastric lesion formation via myeloid-biased differentiation in bone marrow under chronic IL-1β overexpression and <i>Helicobacter felis</i> infection

Background: BRCA2 plays a crucial role in DNA homologous recombination repair, and mutations in this gene significantly increase cancer risk. Previous studies have shown that heterozygous mutations in BRCA2 enhance pancreatic tumorigenesis driven by KRASG12D, but their impact on gastric tissues is less understood. This study investigates how knockout of a single BRCA2 allele affects inflammation-induced gastric damage under chronic interleukin-1β (IL-1β) overexpression and Helicobacter felis infection. Methods: Mice heterozygous for BRCA2 were crossed with ATP4b-IL1β transgenic mice, which overexpress IL-1β in parietal cells to mimic chronic gastric inflammation. These BRCA2+/-; ATP4b-IL1β mice were then infected with H. felis for three months and compared to ATP4b-IL1β control mice. Stomach histology and immune response dynamics were assessed, including a complete blood count (CBC) and flow cytometry of bone marrow to analyze hematopoietic stem cells (HSCs), myeloid-biased multipotent progenitors (MPP3), and neutrophils. Results: We observed no significant atrophy or metaplasia histological changes in the stomachs of BRCA2+/-; ATP4b-IL1β or ATP4b-IL1β mice at three months. However, H. felis infection significantly intensified gastric inflammation, metaplasia, dysplasia, and atrophy in BRCA2+/-; ATP4b-IL1β mice compared to the ATP4b-IL1β mice. CBC results showed a 52.3% increase in neutrophil counts in the blood of infected of infected BRCA2+/-; ATP4b-IL1β mice. Flow cytometry of bone marrow hematopoietic cells indicated a 72.3% reduction in HSCs and a 21.0% increase in MPP3 populations in BRCA2+/- mice compared to BRCA2+/+ mice overexpressing IL-1β, suggesting a shift towards myeloid differentiation. Analysis of gastric tissue showed a 77.9% increase in neutrophil infiltration in BRCA2+/- mice, which correlated with the increased severity of lesions. Conclusions: Our results indicate that heterozygosity for BRCA2 mutations can worsen gastric injuries in the context of chronic inflammation and H. felis infection, potentially due to hematopoietic imbalances and a shift towards neutrophil differentiation that exacerbates gastric pathology. This underscores the critical role of bone marrow dysfunction in driving inflammation-induced gastric damage in individuals with BRCA2 mutations. Future studies are needed to clarify the effects of BRCA2 mutations on hematopoietic progenitors and potential strategies to mitigate these effects. Citation Format: Feijing Wu, Quin Waterbury, Puran Zhang, Hiroki Kobayashi, Biyun Zheng, Hualong Zheng, Yi Zeng, Ruhong Tu, Jin Qian, Xiaofei Zhi, Yosuke Ochiai, Mashahiro Hata, Leah B. Zamechek, Timothy C. Wang. Germline BRCA2 heterozygosity drives gastric lesion formation via myeloid-biased differentiation in bone marrow under chronic IL-1β overexpression and Helicobacter felis infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3445.