The long-range goal of this program project is to improve our understanding of the pathogenesis and pathophysiology of childhood cancers, and to capitalize on the insights gained from these basic studies to device new means of assessing prognosis and improving therapy. This broad objective is being pursued through four interactive projects whose goal is to define the mechanisms by which chimeric transcription factors and altered tumor suppressors contribute to the pathogenesis of childhood cancer. Specifically, this program will examine the translocation-encoded fusion oncoprotein AML1-ETO and Pax3-FKHR and the ARF/Mdm2/p53 tumor suppressor pathway. Together, these genetic abnormalities represent the underlying lesions in a variety of common pediatric malignancies, including leukemias, soft tissue sarcomas, and epithelial tumors. The focus of Project 1 (M. Roussel) is to understand how p16/INK4a and ARF mediate tumor suppressive functions in different physiologic contexts, by studying their regulation, downstream targets and genetic modifier. Project 2 (J. Downing) seeks to define the molecular pathway by which alterations of AML1 leads to leukemia, by defining the spectrum of mutations that cooperate with the t(8;21)- encoded AML1-ETO oncoprotein to induce leukemia, and determine how point mutations in AML1 predispose hematopoietic stem cells to leukemic transformation. Project 3 (G. Grosveld) will use biochemical, cell biological and mouse experiments to determine how Pax3-FKHR acts as an activated oncogene in alveolar rhabdomyosarcoma, and to identify the secondary genetic alterations that are required to cooperate with Pax3-FKHR to induce a full tumor phenotype. In Project 4 (G. Zambetti) will directly examine the biochemical and biophysical properties of a novel germline p53 mutation (p53R337H) that has identified in a cluster of pediatric patients in Southern Brazil with adrenal cortical carcinoma (ACC). These patients lack features of Li-Fraumenia syndrome, suggesting that p53R337H is predisposing patients to ACC. To test this hypothesis, Dr. Zambetti will directly examine the biochemical and biophysical properties of this mutant p53 protein, and will develop mice that contain this mutation in the germline. The proposed research is supported by an Administrative Core and three scientific Core's that provide assistance in the generation of genetically modified mice and the subsequent analysis of these animals through a Pathology Core and a Microarray Gene Expression Laboratory. Through this coordinated program of research, we anticipate substantial progress toward the ultimate goal of improving the treatment of children with cancer.
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