Our long term goal is to understand the role of dysregulated Notch signaling in the pathogenesis of T cell[unreadable] leukemia and to develop new diagnostic, prognostic, and therapeutic strategies based on this information.[unreadable] Recently, Notch mutations have been associated with more than half of human T-ALL, suggesting that[unreadable] advances in understanding leukemogenic Notch signaling will have a significant impact on this disease. Over[unreadable] the last decade, we have developed mouse models, tissue culture assays, and biochemical methods to[unreadable] investigate the role of Notch signaling in T cell leukemia. Here, we will build on these findings to determine[unreadable] whether mutant forms of Notchl drive ectopic T cell development and induce leukemias in mice, and will[unreadable] correlate these outcomes with primary effects of various Notchl alleles on defined subsets of hematopoietic[unreadable] progenitors. Notchl appears to have a broad capacity to collaborate with a number of other transcription[unreadable] factors linked to human T-ALL development. We will determine the ability of these mutated Notch alleles to[unreadable] synergize with other genes commonly implicated in human T-ALL, such as Hox 11, Hox11L and Tall.[unreadable] Finally, Notchl's leukemogenic activity has been linked to up-regulation of unknown downstream target[unreadable] genes. Using a series of well-controlled expression profiling experiments and novel Notch-dependent T-ALL[unreadable] cell lines, we will identify downstream target genes that contribute to the sustained growth of T-ALL cells.[unreadable] Together, these studies will provide a deeper understanding of the pathogenesis of Notch-induced leukemia,[unreadable] and thereby move us closer to novel therapeutic interventions in this disease and other pathologic states[unreadable] characterized by aberrant Notch signaling.[unreadable] The specific aims of this proposal are:[unreadable] 1. To determine the transforming ability of the recently identified Notchl HD and/or PEST mutations[unreadable] 2. To determine how Notchl signals of varying strength interact with other transcription factors to induce TALL[unreadable] 3. To determine the mechanism(s) by which oncogenic Notchl promotes transformation