Improvements in survival have been achieved for children and adolescents with acute myeloid leukemia (AML), with the 5-year survival rates increasing from less than 20% to more than 70%.[1] However, in the past decade, outcome has not improved and remains dismal for high-risk patients. Activating mutations of FLT3 are the most common somatic mutations observed in AML, occurring in approximately 15% of childhood cases, and are associated with a high risk of relapse.[2–4] To facilitate better outcomes for pediatric AML, development and implementation of preclinical in vivo models that faithfully recapitulate the human disease are imperative to enhance the predictive power of novel therapeutics and treatment strategies.

Successful xenotransplantation of primary AML cells from both adult and pediatric patients into immunodeficient mice have been reported.[5–8] However, a recent report revealed an unexpected shift in the clonal architecture, in which a distinct clone, not necessarily the major clone, demonstrated greater engraftment potential and became the predominate clone in vivo.[5] Despite reports suggesting more favorable engraftment rates for primary adult AML samples harboring FLT3 mutations, including internal tandem duplications (ITD),[8] presence of FLT3 mutations did not confer preferential engraftment and were often absent in the engrafting population.[5] These observations have major consequences in the utility of patient-derived xenograft (PDX) models to evaluate novel therapeutics, especially in regard to targeted agents, and supports a need to genetically evaluate the engrafting population to ensure faithful modeling of each human