The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated with human liposarcomas. The altered expression of FUS-CHOP has been implicated in a characteristic subgroup of human liposarcomas. We have introduced the FUS-CHOP transgene into the mouse genome in which the expression of the transgene is successfully driven by the elongation factor 1a (EF1a) promoter to all tissues. The consequent overexpression of FUS-CHOP results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-speci®c genes and a concordant block in the di erentiation program. We have demonstrated that liposarcomas in the FUS-CHOP transgenic mice express high levels of the adipocyte regulatory protein PPARg, whereas it is not expressed in embryonic ®broblasts from these animals following induction to di erentiation toward the adipocyte lineage, indicating that the in vitro system does not really re¯ect the in vivo situation and the developmental defect is downstream of PPARg expression. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1a promoter. This establishes FUS-CHOP overexpression as a key determinant of human liposarcomas and provide the ®rst in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumor.
The most common chromosomal translocation in liposarcomas, t(12;16)(q13;p11), creates the FUS/TLS-CHOP fusion gene. We previously developed a mouse model of liposarcoma by expressing FUS-CHOP in murine mesenchymal stem cells. In order to understand how FUS-CHOP can initiate liposarcoma, we have now generated transgenic mice expressing altered forms of the FUS-CHOP protein. Transgenic mice expressing high levels of CHOP, which lacks the FUS domain, do not develop any tumor despite its tumorigenicity in vitro and widespread activity of the EF1a promoter. These animals consistently show the accumulation of a glycoprotein material within the terminally di erentiated adipocytes, a characteristic ®gure of liposarcomas associated with FUS-CHOP. On the contrary, transgenic mice expressing the altered form of FUS-CHOP created by the in frame fusion of the FUS domain to the carboxy end of CHOP (CHOP-FUS) developed liposarcomas. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1a promoter. The characteristics of the liposarcomas arising in the CHOP-FUS mice were very similar to those previously observed in our FUS-CHOP transgenic mice indicating that the FUS domain is required not only for transformation but also in¯uences the phenotype of the tumor cells. These results provide evidence that the FUS domain of FUS-CHOP plays a speci®c and critical role in the pathogenesis of liposarcoma. Oncogene (2000) 19, 6015 ± 6022.
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