Genetic model systems such as Drosophila have been useful in determining the contribution of normal and abnormal stem cells to the initiation of cancer and in identifying the molecular events that might drive such transformation. Research results on Drosophila neural stem cells imply a causative link between impaired stem-cell division and brain tumor formation supporting the hypothesis that impaired cell-fate determination is a major cause of cancerous overgrowth. However, the cellular and molecular events that operate in these stem cell lineages during normal and abnormal proliferation are poorly understood. Recently, novel vertebrate-like transit-amplifying neural stem cell lineages have been identified in the Drosophila brain, and current data indicates that these lineages are highly vulnerable to tumorigenesis caused by the impairment of tumor suppressor genes controlling cell fate determination. We will focus on these identified neural stem cell lineages and carry out a cellular and molecular genetic analysis of normal and abnormal proliferation in this stem cell model system. Our main goals will be to uncover the cellular and molecular mechanisms that are responsible for the high oncogenic vulnerability of these amplifying neural stem cell lineages and, based on this analysis, to design and test molecular genetic strategies to prevent tumorigenesis of these neural stem cells in vivo, in vitro, and in a host environment. Given the remarkable evolutionary conservation of fundamental mechanisms in stem cell biology, this research should be useful for designing, testing and implementing novel strategies aimed at preventing neural stem cell-derived brain tumors in human stem cell transplantation therapy.