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The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour

Nature Genetics volume 17, pages 309313 (1997) | Download Citation

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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 cells1. 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 represser 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 sites5,6. 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.

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Affiliations

  1. Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

    • Sean Bong Lee
    • , Kim Nichols
    • , Christoph Englert
    • , Shyamala Maheswaran
    •  & Daniel A. Haber
  2. Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.

    • Kathryn Ann Kolquist
    • , Marc Ladanyi
    •  & William L. Gerald
  3. Departments of Human Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.

    • Marc Ladanyi

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Correspondence to Daniel A. Haber.

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https://doi.org/10.1038/ng1197-309