Animal models for the study of childhood leukemia: considerations for model identification and optimization to...

Leukemias are the most common pediatric malignancies diagnosed in western industrialized societies. In spite of the substantial incidence of childhood leukemia in the United States and other countries, neither epidemiology studies conducted in human populations nor hazard identification studies conducted using traditional animal models have identified environmental or other factors that are directly linked to increased risk of disease. Molecular biology data and mathematical modeling of incidence patterns suggest that pediatric leukemogenesis may occur through a multistage or "multihit" mechanism that involves both in utero and postnatal events. The authors propose that pediatric leukemias can be modeled experimentally using a "multihit" paradigm analogous to the "initiation-promotion" and "complete carcinogenesis" models developed for tumor induction in mouse skin and rat liver. In this model for childhood leukemia, an initial genetic alteration occurs during in utero or early postnatal development, but clinical disease develops only upon additional genetic or nongenetic events that occur during the postnatal period. Application of this multistage or "multihit" model to hazard assessment studies conducted in transgenic or knockout mice carrying relevant molecular lesions may provide a sensitive approach to the identification of environmental agents that are important risk factors for childhood leukemia.