A number of genes whose products regulate animal development are also targets for acquired mutations in human cancers. However, the pathogenetic connections between disrupted development and cancer are poorly understood at a molecular level. Notch 1 and Pbx1 are examples of proto-oncogenes that contributes to cell fate specification in development and are disrupted by mutations in a subst of lymphoid cancers. Notch proteins are cell surface receptors that engage a distinct family of cellular ligands to initiate transcriptional cascades which amplify and consolidate molecular differences to dictate cell fates during development. Pbx1 is a homeodomain transcription factor that dimerizes with a wide group of Hox proteins and critically contributes to the segment-specific execution of Hox developmental programs during embryogenesis. In preliminary studies we have obtained genetic evidence for a potential connection between the Notch and Pbx-Hox signaling pathways in oncogenesis in oncogenesis. Studies in this project will investigate whether ectopic expression of Notch ligands activates the Notch signaling pathway in lymphoid malignancies, and in particular whether this may be a requirement for oncogenic transformation by the lymphoid oncoprotein E2a-Pbx1. In our first specific aim we will determine the normal expression profiles for Notch ligands during B cell differentiation and investigate whether they are perturbed in neoplastic lymphocytes particularly those harboring translocations involving Pbx1. In the second aim we will use retroviral- mediated gene transfer techniques to determine if forced expression of Notch ligands is oncogenic in primary hematopoietic cells, in vitro and in vivo. In the third specific aim, the Notch signaling pathway will be blocked using dominant negative receptor mutants to determine if signaling through the Notch pathway is necessary for the oncogenic properties of E2a-Pbx1 and other lymphoid oncoproteins that ectopically induce ligand expression. Finally, studies in the fourth specific aim will focus on the identification of novel upstream regulators of Notch ligand expression in lymphocytes using a genetic screen to search for genes that accelerates oncogenesis in Notch transgenic mice. These studies will establish the prevalence of Notch ligand alterations in lymphoid oncogenesis, identify their upstream regulators, and define the molecular interplay between Notch and Pbx-Hox signaling pathways. They may also provide new reagents for the improved diagnosis and longitudinal monitoring of patients with lymphoid malignancies and establish models for the evaluation of newer generations of anti- neoplastic therapies.
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