Abstract B048: Loss of Bmi1 disrupts regeneration of the pancreas after injury

Abstract The pancreas has a remarkable ability to recover after acute pancreatitis; this process is tightly regulated and involves a transition through acinar-to-ductal metaplasia (ADM) to mitigate damage during the early stages of injury. The Polycomb repressor complex 1 (PRC1) subunit BMI1 (B-cell Moloney murine leukemia virus integration site 1) is required for regeneration of the murine pancreas after pancreatitis and plays a role in pancreatic cancer initiation. Correlative studies have also shown that high levels of BMI1 in PDAC patients are associated with poor prognosis. Previous studies suggest that BMI1 is only expressed by a subset of acinar cells that contribute to tissue homeostasis and renewal of the pancreas. However, the exact role of BMI1 during stress and recovery of the pancreas is currently unknown. Here we investigate the dynamics of Bmi1 expression at baseline, during injury and recovery by RNA in situ hybridization (RNAScope) and assess the effects of Bmi1 loss on the different stages of regeneration of the pancreas after injury histologically. We also characterize the immune infiltrate in the presence and absence of Bmi1 after acute pancreatitis. Our data indicates that Bmi1 is expressed in all acinar cells at baseline and transcript levels are upregulated early in response to caerulein-induced pancreatitis. ADM levels peak histologically within 48 hours and reversal starts within 72 hours in wildtype mice. Recovery of the pancreas is dysregulated in Bmi1 knockout mice at the same timepoints - >50% of Bmi1 null and Bmi1 heterozygotes do not histologically recover after pancreatitis and have large areas of tissue with ADM, 7 days post caerulein induced pancreatitis, compared to 100% recovery in Bmi1 wildtype pancreata. The number of Bmi1 mRNA transcripts per cell increases after damage and decreases as the pancreas regenerates, approaching baseline levels as the pancreas recovers fully. Residual numbers of macrophages are found in the regenerated wildtype pancreas, whereas Bmi1-deficient pancreata have persistent infiltrate, especially in damaged regions. The same holds true for infiltrating T-cells. Together, this data suggests that BMI1 is important for the regulation of pancreatic homeostasis and regeneration and the pancreatic microenvironment Citation Format: Joyce K. Thompson, Nur M. Renollet, Emily Wu, Nina G. Steele, Filip Bednar. Loss of Bmi1 disrupts regeneration of the pancreas after injury [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B048.