title: Engraftment of low numbers of pediatric acute lymphoid and myeloid leukemias into NOD/SCID/IL2Rcγnull mice reflects individual leukemogenecity and highly correlates with clinical outcome.
abstract: 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 (p ≤ 0.004). 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.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Woiterski
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.forename: Kai E
authors.initials: KE
authors.lastname: Witte
authors.forename: Barbara
authors.initials: B
authors.lastname: Goecke
authors.forename: Vanessa
authors.initials: V
authors.lastname: Heininger
authors.forename: Martin
authors.initials: M
authors.lastname: Philippek
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Andre
authors.initials: A
authors.lastname: Schrauder
authors.forename: Silja
authors.initials: S
authors.lastname: Röttgers
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
authors.forename: Maya C
authors.initials: MC
authors.lastname: André
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology / Q000401:mortality; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit
keywords: NSG mice; pediatric leukemias; xenotransplantation