title: The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour.
abstract: Chromosomal translocations resulting in chimaeric transcription factors underlie specific malignancies, but few authentic target genes regulated by these fusion proteins have been identified. Desmoplastic small round-cell tumour (DSRT) is a multiphenotypic primitive tumour characterized by massive reactive fibrosis surrounding nests of tumour cells. The t(11;22)(p13;q12) chromosomal translocation that defines DSRT produces a chimaeric protein containing the potential transactivation domain of the Ewing-sarcoma protein (EWS) fused to zinc fingers 2-4 of the Wilms tumour suppressor and transcriptional repressor WT1 (refs 2,3). By analogy with other EWS fusion products, the EWS-WT1 chimaera may encode a transcriptional activator whose target genes overlap with those repressed by WT1 (ref. 4). To characterize its functional properties, we generated osteosarcoma cell lines with tightly regulated inducible expression of EWS-WT1. Expression of EWS-WT1 induced the expression of endogenous platelet-derived growth factor-A (PDGFA), a potent secreted mitogen and chemoattractant whose promoter contains the many potential WT1-binding sites. Native PDGFA was not regulated by wild-type WT1, indicating a difference in target gene specificity between this tumour suppressor and its oncogenic derivative. PDGFA was expressed within tumour cells in primary DSRT specimens, but it was absent in Wilms tumours expressing WT1 and Ewing sarcomas with an EWS-Fli translocation. We conclude that the oncogenic fusion of EWS to WT1 in DSRT results in the induction of PDGFA, a potent fibroblast growth factor that contributes to the characteristic reactive fibrosis associated with this unique tumour.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown.
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.forename: K A
authors.initials: KA
authors.lastname: Kolquist
authors.forename: K
authors.initials: K
authors.lastname: Nichols
authors.forename: C
authors.initials: C
authors.lastname: Englert
authors.forename: S
authors.initials: S
authors.lastname: Maheswaran
authors.forename: M
authors.initials: M
authors.lastname: Ladanyi
authors.forename: W L
authors.initials: WL
authors.lastname: Gerald
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D001665:Binding Sites; D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D015972:Gene Expression Regulation, Neoplastic; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034802:RNA-Binding Protein EWS; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics*; D013752:Tetracycline / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; C106032:EWS1-WT1 fusion protein, human; D051766:Early Growth Response Protein 1; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D017874:Immediate-Early Proteins; D015514:Oncogene Proteins, Fusion; D010982:Platelet-Derived Growth Factor; D034802:RNA-Binding Protein EWS; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; C075278:platelet-derived growth factor A; D013752:Tetracycline