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Molecular and Cellular Biology, January 2003, p. 482-492, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.482-492.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Alteration of Mesodermal Cell Differentiation by EWS/FLI-1, the Oncogene Implicated in Ewing's Sarcoma

Susan Eliazer,1 Jeffrey Spencer,2 Dan Ye,1 Eric Olson,2 and Robert L. Ilaria Jr.1*

Division of Hematology-Oncology, Department of Medicine, Simmons Cancer Center and Hamon Center for Therapeutic Oncology Research,1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas2

Received 13 May 2002/ Returned for modification 17 July 2002/ Accepted 15 October 2002

The chimeric fusion gene EWS/FLI-1 is detected in most cases of Ewing's sarcoma (ES), the second most common malignant bone tumor of childhood. Although 80% of ES tumors develop in skeletal sites, the remainder can arise in almost any soft tissue location. The lineage of the cell developing the EWS/FLI-1 gene fusion has not been fully characterized but is generally considered to be of either mesenchymal or neural crest origin. To study this oncogene in a conceptually relevant target cell, EWS/FLI-1 was introduced into the murine cell line C2C12, a myoblast cell line capable of differentiation into muscle, bone, or fat. In this cellular context, EWS/FLI-1 profoundly inhibited the myogenic differentiation program. The block in C2C12 myogenic differentiation required the nuclear localization and DNA-binding functions of EWS/FLI-1 and was mediated by transcriptional and posttranscriptional suppression of the myogenic transcription factors MyoD and myogenin. Interestingly, C2C12-EWS/FLI-1 cells constitutively expressed alkaline phosphatase, a bone lineage marker, and were alkaline phosphatase positive by histochemistry but showed no other evidence of bone lineage commitment. Consistent with recent findings in human ES tumor cell lines, C2C12-EWS/FLI-1 cells constitutively expressed cyclin D1 and demonstrated decreased expression of the cell cycle regulator p21cip1, even under differentiation conditions and at confluent density. This C2C12-EWS/FLI-1 cell model may assist in the identification of novel differentially expressed genes relevant to ES and provide further insight into the cell(s) of origin developing ES-associated genetic fusions.

* Corresponding author. Mailing address: Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., MC 8593, Dallas, TX 75390-8593. Phone: (214) 648-1632. Fax: (214) 648-4940. E-mail: Robert.Ilaria{at}utsouthwestern.edu.

Molecular and Cellular Biology, January 2003, p. 482-492, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.482-492.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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