Divergent Ewing's sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells

Ewing's sarcomas express chimeric transcription factors resulting from a fu sion of the amino terminus of the EWS gene to the carboxyl terminus of one of five ETS proteins. While the majority of tumors express EWS/FLI1 fusions , some Ewing's tumors contain variant chimeras such as EWS/ETV1 that have d ivergent ETS DNA-binding domains. In spite of their structural differences, both EWS/ETS fusions up regulate EAT-2, a previously described EWS/FLI1 ta rget gene. In contrast to EWS/FLI1, NIH3T3 cells expressing EWS/ETV1 cannot form colonies in soft agar though coexpression of a dominant negative trun cated ETV1 construct attenuates EWS/FLI1 mediated anchorage independent gro wth. When EWS/ETV1 or EWS/FLI1 expressing NIH3T3 cells are injected into SC ID mice, tumors form more often and faster than with NIH3T3 cells with empt y vector controls. The tumorigenic potency of each EWS/ETS fusion is linked to its C-terminal structure, with the FLI1 C-terminus confering a greater tumorigenic potential than the corresponding ETV1 domain. The resulting EWS /ETV1 and EWS/FLI1 tumors closely resemble each other at both a macroscopic and a microscopic level. These tumors differ greatly from tumors formed by NIH3T3 cells expressing activated RAS, These data indicate that in spite o f their structural differences, EWS/ETV1 and EWS/FLI1 promote oncogenesis v ia similar biologic pathways.