The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour Journal Article
| Authors: | Lee Bong, S.; Kolquist, K. A.; Nichols, K.; Englert, C.; Maheswaran, S.; Ladanyi, M.; Gerald, W. L.; Haber, D. A. |
| Article 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-Fll 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. |
| Keywords: | immunohistochemistry; osteosarcoma; platelet derived growth factor; controlled study; human cell; dna-binding proteins; transcription factor; transcription, genetic; tumor cells, cultured; transcription factors; ewing sarcoma; chimera; in situ hybridization; gene expression regulation, neoplastic; recombinant proteins; platelet-derived growth factor; oncogene proteins, fusion; ribonucleoproteins; translocation, genetic; binding sites; malignant transformation; tetracycline; blotting, northern; immediate-early proteins; nephroblastoma; immunofluorescence microscopy; rna-binding protein ews; repressor gene; chromosome translocation 11; suppressor gene; gene isolation; promoter regions (genetics); early growth response protein 1; chromosome translocation 22; heterogeneous-nuclear ribonucleoproteins; humans; human; priority journal; article; chimaera |
| Journal Title: | Nature Genetics |
| Volume: | 17 |
| Issue: | 3 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1997-11-01 |
| Start Page: | 309 |
| End Page: | 313 |
| Language: | English |
| DOI: | 10.1038/ng1197-309 |
| PUBMED: | 9354795 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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