Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells Results in EWS/FLI-1-dependent, ewing sarcoma-like tumors.

Abstract

Ewing sarcoma is the second most common malignant pediatric bone tumor. Over 80% of Ewing sarcoma contain the oncogene EWS/FLI-1, which encodes the EWS/FLI-1 oncoprotein, a hybrid transcription factor comprised of NH2-terminal sequences from the RNA-binding protein EWS and the DNA-binding and COOH-terminal regions of the Ets transcription factor FLI-1. Although numerous genes are dysregulated by EWS/FLI-1, advances in Ewing sarcoma cancer biology have been hindered by the lack of an animal model because of EWS/FLI-1-mediated cytotoxicity. In this study, we have developed conditions for the isolation and propagation of murine primary bone-derived cells (mPBDC) that stably express EWS/FLI-1. Early-passage EWS/FLI-1 mPBDCs were immortalized in culture but inefficient at tumor induction, whereas later-passage cells formed sarcomatous tumors in immunocompetent syngeneic mice. Murine EWS/FLI-1 tumors contained morphologically primitive cells that lacked definitive lineage markers. Molecular characterization of murine EWS/FLI-1 tumors revealed that some but not all had acquired a novel, clonal in-frame p53 mutation associated with a constitutive loss of p21 expression. Despite indications that secondary events facilitated EWS/FLI-1 mPBDC tumorigenesis, cells remained highly dependent on EWS/FLI-1 for efficient transformation in clonogenic assays. This Ewing sarcoma animal model will be a useful tool for dissecting the molecular pathogenesis of Ewing sarcoma and provides rationale for the broader use of organ-specific progenitor cell populations for the study of human sarcoma.

• Authors: Yeny Castillero-Trejo, Susan Eliazer, Lilin Xiang, James A Richardson, Robert L Ilaria Jr
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 19 Pg. 8698-705 (Oct 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16204038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fli1 protein, mouse
• Oncogene Proteins, Fusion
• Proto-Oncogene Protein c-fli-1
• RNA-Binding Protein EWS

Topics

• Amino Acid Sequence
• Animals
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Cycle (physiology)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Disease Models, Animal
• Gene Expression
• Mice
• Mice, Inbred BALB C
• Molecular Sequence Data
• Oncogene Proteins, Fusion (biosynthesis, genetics)
• Proto-Oncogene Protein c-fli-1 (biosynthesis, genetics)
• RNA-Binding Protein EWS (biosynthesis, genetics)
• Sarcoma, Ewing (genetics, metabolism, pathology)