DISSECTION OF ONCOGENIC PATHWAYS USING DROSOPHILA

DESCRIPTION: (Applicant's Description) The long-term goal of this project is to characterize the genetic pathways controlled by dominantly acting oncogenes. To carry out these studies the model organism, Drosophila melanogaster, will be used because of the ability to carry out powerful genetic screens. The AML-ETO oncogene, which is responsible for a significant fraction of Acute Myeloid Leukemias, will be the focus of these studies. The immediate specific aims are to: 1) characterize the wild type function of the ETO ortholog in Drosophila, called nervy; 2) to characterize the gain-of-function phenotypes that are induced in Drosophila by expressing Nervy and AML-ETO proteins. In addition, the activities of chimeric proteins that are analogous to AML-ETO, but are constructed from the orthologous Drosophila genes, will also be characterized. 3) Once these data are in hand, genetic screens will be conducted in Drosophila to identify genes that interact with Nervy and AML-ETO in vivo. These screens will be identify components of the genetic pathways in which Nervy and AML-ETO function. Once additional components of these pathways have been identified, their relevance to leukemogenesis will be tested. If confirmed, these genes will provide additional targets for the development of anti-cancer drugs and other potentially novel therapies. Moreover, if successful, this approach may set a precedent for analyzing the genetic pathways in which other dominantly acting oncogenes function. The use of Drosophila genetics is proposed to help make connections between genetic functions that cannot be easily identified in mammalian experimental systems.