Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 133, Issue 7, Pages 1547-1556Publisher
WILEY
DOI: 10.1002/ijc.28170
Keywords
xenotransplantation; NSG mice; pediatric leukemias
Categories
Funding
- Deutsche Forschungsgemeinschaft [KFO 183, TP 4, TP 6]
- Faculty of Medicine of Tuebingen [IZKF 1686-0-0, 1876-0-0, 1951-0-0]
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Although immortalized cell lines have been extensively used to optimize treatment strategies in cancer, the usefulness of such in vitro systems to recapitulate primary disease is limited. Therefore, the design of in vivo models ideally utilizing patient-derived material is of critical importance. In this regard, NOD.Cg-Prkdc(scid)IL2rg(tmWjl)/Sz (NSG) mice have been reported to provide superior engraftment rates. However, limited data exist on the validity of such a model to constitute a surrogate marker for clinical parameters. We studied primary and serial engraftment on more than 200 NSG mice with 54 primary pediatric B cell precursor acute lymphatic leukemia (B-ALL), myeloid leukemia (AML) and T cell leukemia (T-ALL) samples, characterized the leukemogenic profile and correlated engraftment kinetics with clinical outcome. Median time to engraftment was 7-10 weeks and 90% of the mice engrafted. Male recipients conferred significantly higher engraftment levels than female recipients (p0.004). PCR-based minimal residual disease marker expression and fluorescence in situ hybridization confirmed the presence of patient-specific genetic aberrations in mice. Transcriptome cluster analysis of genes known to be important in the leukemogenesis of all three diseases revealed that well-known tumor-regulating genes were expressed to a comparable extent in mice and men. The extent of engraftment and overall survival of NSG mice highly correlated with the individual prognosis of B-ALL, AML and T-ALL patients. Thus, we propose an in vivo model that provides a valuable preclinical tool to explore the heterogeneity of leukemic disease and exploit patient-tailored leukemia-targeting strategies within multivariate analyses. What's new? Humanized mice are powerful tools to study human immune cells in vivo. The authors describe the engraftment of 54 pediatric leukemia samples in a cohort of nonobese mice with specific T, B and NK cell deficiency (NSG). Remarkably, they show that the patient-derived samples retain their leukemogenic profile within the reconstituted mice. In addition, they find a specific correlation between the survival of individual mice and the prognosis of the pediatric donor patients, indicating that this model could serve as a preclinical tool to explore individualized treatment options.
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