Abstract 48: Enhanced patient derived xenotransplantation of TP53 mutant and splicing factor mutant acute myeloid leukemia in super immunodeficient NOG-EXL mice

Abstract Xenotransplantation of acute myeloid leukemia (AML) cells is an established model for preclinical development and understanding of AML biology. AML xenotransplantation has been well characterized in highly immunocompromised NSG mice, but time to engraftment in this strain is often prolonged and some AML types engraft poorly. In particular, we have found that TP53 mutant AML and splicing factor mutant AML engraft poorly in NSG mice. Alternative mouse models are NSG-SGM3 (SGM3) and NOG-EXL mice, which combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines. However, the SGM3 strain is prone to highly variable time to and level of engraftment as well as spontaneous animal death. To address these concerns, we compared AML primary sample engraftment in the NSG, SGM3, and NOG-EXL. First, we studied overall survival in SGM3 mice compared to NOG-EXL mice engrafted with 4 separate AML’s (n=5 per cohort). Consistent with previous results, 25% of SGM3 mice engrafted with AML became ill and required sacrifice approximately 5 weeks after injection. This did not correlate with the level of AML engraftment. In contrast, only one NOG-EXL mouse became ill during 12 weeks of observation. We next studied relative engraftment in all 3 strains of five TP53 mutant AML samples that had either previously not engrafted or engrafted poorly in NSG mice. We aspirated bone marrow on all mice five weeks after injection. Level of engraftment across strains varied from not detectable in NSG mice to over 80% in NOG-EXL and SGM3 mice. Mice were observed until symptoms of leukemia engraftment developed (42 to 77 days) at which time mice were sacrificed and analyzed for leukemic burden by measuring huCD45+huCD33+ cells in bone marrow and spleen. Interestingly, bone marrow burden increased in NSG mice over time although total mouse leukemic burden in NSG mice was consistently lower than in the SGM3 and NOG-EXL mice. Comparing leukemic burden in NOG-EXL to SGM3 mice showed a modestly higher leukemic burden in NOG-EXL at time of sacrifice. Human CD45+ and human CD33+ cell expression, as assessed by flow cytometry, were higher in SGM3 and NOG-EXL compared to NSG mice. We also found that splicing factor mutant AML engrafted poorly in NSG mice, and preliminary analysis suggests similar results with shorter time to engraftment and higher levels of engraftment in NOG-EXL and SGM3 mice. Again, no early deaths were seen in the NOG-EXL strain. Overall, these results support the hypothesis that the NOG-EXL strain is an improved strain for use in AML xenotransplantation compared to NSG and NSG-SGM3, with enhanced levels of engraftment without spontaneous mortality. Data on relative response to cytotoxic and venetoclax therapies is ongoing. Citation Format: Tanmoy Sarkar, Sarah Skuli, Nicolas Skuli, Martin Keogh, Anthony Secreto, Moriah Jacobson, Martin Carroll. Enhanced patient derived xenotransplantation of TP53 mutant and splicing factor mutant acute myeloid leukemia in super immunodeficient NOG-EXL mice [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 48.