The purpose of this proposal is to facilitate the transition of Dr. Michael Laiosa from a mentored postdoctoral research position to an independent academic research scientist. In pursuit of the goal of establishing independence, Dr. Laiosa has proposed to translate findings from human epidemiological studies to a murine model of dioxin-induced T-cell leukemia. This murine model will be used to determine the underlying mechanism(s) of the environmental basis for T-cell acute lymphoblastic leukemia (T-ALL) formation and progression. The relevance to public health is that this model will be employed for a pre-clinical evaluation of the dietary and chemopreventative agent resveratrol, which has the potential to prevent the initiation and/or recurrence of T-cell leukemia in individuals with elevated cancer risk. Moreover, approximately 208,000 people in the United States are currently living with leukemia and approximately 22,000 people a year will die from the disease. Dozens of genetic risk factors for leukemic diseases have been identified, and a number of environmental agents have been shown to increase cancer risk, including 2,3,7,8 -tetrachlordibenzo-pdioxin (TCDD) and dioxin-like compounds, which humans are exposed to at low levels on a daily basis. Understanding, how environmental factors affect the development and progression of leukemia not only represents a significant gap in our knowledge but will also provide Dr. Laiosa with additional training in a new field for him (leukemia) using his extensive experience in the field of thymocyte development and developmental immunotoxicology as a framework. Specifically, this proposal will attempt to define how TCDD interacts with mutations in the Notch protein potentially leading to T-ALL. Mutations in Notch have been identified in more than 70% of patients with T-ALL. This proposal will determine how TCDD activation of the Aryl hydrocarbon receptor (AHR) potentially modulates Notch activity by testing the following three specific aims: 1) test the hypothesis that during thymocyte development, ligand activation of the AHR synergizes with the Notch protein, modulating gene expression, cell cycle regulation, and apoptotic regulation; 2) test the hypothesis that AHR expression and/or activation by environmental agents interacts with activated Notch' 1 promoting T-leukemeogenesis; 3) test the hypothesis that the chemo-preventative agent resveratrol antagonizes AHR dependent toxicity and inhibits T-ALL leukemeogenesis.
