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bioRxiv · 10.1101/2022.05.17.492353

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-KrasG12D/+) mice

Walcheck, M. T.·Nukaya, M.·Ranheim, E. A.·Matkowskyj, K. A.·Ronnekleiv-Kelly, S. M.
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Abstract

BackgroundPdx1 expression in pancreatic lineage cells underlies the utility of the KC mouse model (Pdx1-Cre; LSL-KrasG12D/+) for understanding how KrasG12D-mutation drives formation of pancreas cancer precursor lesions and carcinoma. The highly utilized KC model has a reported mortality rate of about 30%, which has been attributed to pancreas cancer, despite lack of substantive evidence. This study describes a novel cause of the early deaths, in which KC mice develop Kras-driven T-cell acute lymphoblastic leukemia (T-ALL). MethodsKC mice and control mice underwent histopathologic examination including thymus, liver, spleen, bone marrow and pancreas, and immunohistochemistry (IHC) was used to confirm leukemia development. A reporter strain (Ai14) was used to identify location of Pdx1-Cre expression and concomitant mutant-Kras activation, which was confirmed using flow cytometry, IHC, immunofluorescence, mRNA analysis, and bone marrow transplant studies. ResultsPdx1 expression in the hematopoietic compartment of KC mice resulted in Cre-recombinase mediated excision of lox-stop and activation of mutant-Kras gene (KrasG12D/+) in the multipotent progenitor cells (MPP), and subsequent development of Kras-mutant T-ALL creating thymic tumors in a subset of mice. Overall, 20% (5/25) of KC mice developed a large thymic tumor due to T-ALL by 9 months of age. Moreover, through isolation and transplantation of pooled bone marrow from KC mice into CD45 congenic mice, 100% of recipient mice were found to develop T-ALL. These results further confirm mutant-Kras expression in the hematologic compartment is driving the development of T-ALL in the KC mouse model. ConclusionsThese results are an essential consideration for investigators while utilizing this model in pancreas cancer studies, particularly when evaluating factors that may coincidentally enhance the formation of KrasG12D-driven T-ALL (e.g. transcription factors impacting hematopoietic cells). Finally, the lower penetrance of T-ALL development in KC mice (compared to existing leukemia models) suggest that the KC mouse could be considered as an alternative research model to evaluate onset and factors that exacerbate development of T-ALL.

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Walcheck, M. T., Nukaya, M., Ranheim, E. A., Matkowskyj, K. A., Ronnekleiv-Kelly, S. M.. 2022-05-19. Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-KrasG12D/+) mice. https://doi.org/10.1101/2022.05.17.492353

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