EWS/FLI-1 Induces Rapid Onset of Myeloid/Erythroid Leukemia in Mice

Abstract

EWS/FLI-1 is a chimeric oncogene generated by chromosomal translocation in Ewing tumors, a family of poorly differentiated pediatric tumors arising predominantly in bone but also in soft tissue. The fusion gene combines sequences encoding a strong transactivating domain from the EWS protein with the DNA binding domain of FLI-1, an ETS transcription factor. A related fusion, TLS/ERG, has been found in myeloid leukemia. To determine EWS/FLI-1 function in vivo, we engineered mice with Cre-inducible expression of EWS/FLI-1 from the ubiquitous Rosa26 locus. When crossed with Mx1-cre mice, Cre-mediated activation of EWS/FLI-1 resulted in the rapid development of myeloid/erythroid leukemia characterized by expansion of primitive mononuclear cells causing hepatomegaly, splenomegaly, severe anemia, and death. The disease could be transplanted serially into naïve recipients. Gene expression profiles of primary and transplanted animals were highly similar, suggesting that activation of EWS/FLI-1 was the primary event leading to disease in this model. The Cre-inducible EWS/FLI-1 mouse provides a novel model system to study the contribution of this oncogene to malignant disease in vivo.

SUPPLEMENTAL MATERIAL

We thank Philippe Soriano (Fred Hutchinson Cancer Center, Seattle, WA) for constructs to generate the ROSA26/EWS/FLI-1 targeting vector and Yaacov Ben David (University of Toronto, Ontario, Canada) for F-MuLV cell lines. We thank Paul Ney (St. Jude Children's Research Hospital) for MEL cells and helpful discussions and Bob Lorsbach, James Downing, and Charles Mullighan for helpful discussions.

This work was supported by Public Health Service grant CA92117 to S.J.B. and by the American Lebanese and Syrian Associated Charities.