The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomasin transgenic mice

The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated w ith human Liposarcomas. The altered expression of FUS-CHOP has been implica ted 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 1 alpha (EF1 alp ha) promoter to all tissues, The consequent overexpression of FUS-CHOP resu lts in most of the symptoms of human liposarcomas, including the presence o f lipoblasts with round nuclei, accumulation of intracellular lipid, induct ion of adipocyte-specific genes and a concordant block in the differentiati on program, We have demonstrated that liposarcomas in the FUS-CHOP transgen ic mice express high Levels of the adipocyte regulatory protein PPAR gamma, whereas it is not expressed in embryonic fibroblasts from these animals fo llowing induction to differentiation toward the adipocyte lineage, indicati ng that the in vitro system does not really reflect the in vivo situation a nd the developmental defect is downstream of PPAR gamma expression. No tumo rs of other tissues were found in these transgenic mice despite widespread activity of the EF1 alpha promoter. This establishes FUS-CHOP overexpressio n as a key determinant of human liposarcomas and provide the first in vivo evidence for a link between a fusion gene created by a chromosomal transloc ation and a solid tumor.