TRANSFORMING ACTIVITY OF THE CHIMERIC SEQUENCE FORMED BY THE FUSION OF COLLAGEN GENE COL1A1 AND THE PLATELET-DERIVED GROWTH-FACTOR B-CHAIN GENE IN DERMATOFIBROSARCOMA PROTUBERANS

As a consequence of a reciprocal translocation t(17;22)(q22;q13) and o f supernumerary ring chromosomes derived from the t(17;22), a fusion b etween the platelet-derived growth factor b-chain (PDGF, c-sis proto-o ncogene) and the collagen type 1A1 (COL1A1) genes has been recently de scribed in dermatofibrosarcoma protuberans (DP), an infiltrating skin tumor (Simon ct al,, 1997), Although PDGFB has been implicated in tran sforming processes via autocrine and paracrine pathways, by the activa tion of the cognate receptor, no direct evidence of its involvement in neoplastic transformation of human tumours has been so far provided. In this report, we have tested the DNA from four DPs in the classical DNA transfection assay onto NIH3T3 fibroblast cell line. All the DNAs induced the formation of transformed foci in the transfected cultures whose derived cell lines were shown to contain a fused sequence compri sing the human COL1A1 and PDGF genes. The relative breakpoint regions have been sequenced revealing that this gene fusion deleted exon 1 of PDGF and released the growth factor from its normal regulation, All th e biochemical and biological assays were consistent with the model of an autocrine mechanism for NIH3T3 transformation by the human rearrang ed PDGFB gene involving the activation of the endogeneous PDGF recepto r.