FUNCTIONAL ROLE OF FLI-1 IN NEOPLASIA

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Characterization of mouse erythroleukemias suggested involvement of at least three ets family members (v-ets, Fli-1 and Spi-1). Last few years we have identified and characterized many members of ets oncogene family. Mouse Fli-1 gene is shown to be rearranged in 75% of erythroleukemias induced by Friend murine leukemia virus. Recently we have cloned and characterized the human Fli-1 gene. Analysis of these cDNA clones revealed that this gene is highly homologous to another ets family member erg, which was previously identified by us. We propose to screen wide variety of human solid tumors and leukemias for possible rearrangements of Fli-1 gene. We intend to compare the normal and aberrant Fli-1 locus to understand the mechanism of activation of human Fli-1 gene. Previously we have shown that erg gene which is highly homologous to Fli- 1 gene, codes for sequence specific DNA binding proteins and also act as transcriptional activators. Therefore we plan to express human Fli-1 gene in bacteria and mammalian cells, identify and characterize the proteins. We intend to study the oncogenic potential of normal and aberrant Fli-1 gene. We also propose to study DNA binding and transcriptional activation properties of Fli-1 gene products and study their role in oncogenic properties of Fli-1 gene. We plan to study the cooperativity of Fli-1 with other nuclear oncogenes and study their effect on their biochemical and biological properties. We intend to study the role of protein-protein interaction on normal and aberrant Fli- 1 proteinsinneoplasia.