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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References
Gerald, W.L. et al. Intra-abdominal desmoplastic small round-cell tumor. Am. J. Surg. Pathol. 15, 499–513 (1991).
Ladanyi, M. & Gerald, W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 54, 2837–2840 (1994).
Gerald, W.L., Rosai, J. & Ladanyi, M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion in desmoplastic small round cell tumor. Proc. Natl. Acad. Sci. USA 92, 1028–1032 (1995).
Rauscher, F.J. III The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J. 7, 896–903 (1993).
Wang, Z., Madden, S., Deuel, T. & Rauscher, F. III The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene.. J. Biol. Chem. 267, 21999–22002 (1992).
Gashler, A. et al. Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms' tumor suppressor WT1. Proc. Natl. Acad. Sci. USA 89, 10984–10988 (1992).
Delattre, O. et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359, 162–165 (1992).
Crozat, A., Åman, P., Mandahl, N. & Ron, D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363, 640–644 (1993).
Zucman, J. et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J. 12, 4481–4487 (1993).
Zucman, J. et al. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nature Genet. 4, 341–345 (1993).
Sorensen, P.H.B. et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWSgene to another ETS-family transcription factor, ERG. Nature Genet. 6, 146–151 (1994).
Englert, C. et al. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J. 14, 4662–4675 (1995).
Zinszner, H., Immanuel, D., Liang, F.-X. & Ron, D.A. topogenic role for the oncogenic N-terminus of TLS: nucleolar localization when transcription is inhibited. Oncogene 14, 451–461 (1997).
Larsson, S.H. et al. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell 81, 391–401 (1995).
Englert, C. et al. Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. Proc. Natl. Acad. Sci. USA 92, 11960–11964 (1995).
May, W.A. et al. The Ewing's sarcoma EWS/Fli-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than Fli-1. Mol. Cell. Biol. 13, 7393–7398 (1993).
Haber, D.A. et al. WT7-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 262, 2057–2059 (1993).
Werner, H. et al. Increased expression of the insulin-like growth factor I receptor gene IGF1R in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product. Proc. Natl. Acad. Sci. USA 90, 5828–5832 (1993).
Werner, H. et al. Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site. J. Biol. Chem. 269, 12577–12582 (1994).
Takimoto, Y., Wang, Z.Y., Kobler, K. & Deuel, T.F. Promoter region of the human platelet-derived growth factor A-chain gene. Proc. Natl. Acad. Sci. USA 88, 1686–1690 (1991).
Rorsman, R., Leveen, P. & Betsholtz, C. Platelet-derived growth factor (PDGF) A-chain mRNA heterogeneity generated by the use of alternative promoters and alternative polyadenylation sites. Growth Factors 7, 241–251 (1992).
Wang, Z., Qiu, Q., Enger, K. & Deuel, T. A second transcriptionally active DNA-binding site for the Wilms tumor gene product, WT1. Proc. Natl. Acad. Sci. USA 90, 8896–8900 (1993).
Reddy, J., Hosono, S. & Licht, J. The transcriptional effect of WT1 is modulated by choice of expression vector. J. Biol. Chem. 270, 29976–29982 (1995).
Heldin, C.-H. Structural and functional studies on platelet-derived growth factor. EMBO J. 11, 4251–4259 (1992).
Seppa, H.E., Grotendorst, G.R., Seppa, S.I., Schiffman, E. & Martin, G.R. Platelet-derived growth factor is chemotactic for fibroblasts. J. Cell Biol. 92, 584–588 (1982).
Vignaud, J.M. et al. The role of platelet-derived growth factor production by tumor-associated macrophages in tumor stroma formation in lung cancer. Cancer Res. 54, 5455–5463 (1994).
Anan, K. et al. Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119, 333–339 (1996).
Eming, S.A. et al. Genetically modified human epidermis overexpressing PDGF-A directs the development of a cellular and vascular connective tissue stroma when transplanted to athymic mice—implications for the use of genetically modified keratinocytes to modulate dermal regeneration. J. Invest. Dermatol. 105, 756–763 (1995).
Cleary, M.L. Oncogenic conversion of transcription factors by chromosomal translocations. Cell 66, 619–622 (1991).
Rabbitts, T.H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994).
Braun, B.S., Frieden, R., Lessnick, S.L., May, W.A. & Denny, C.T. Identification of target genes for the Ewing's sarcoma EWS/Fli fusion protein by representational difference analysis. Mol. Cell. Biol. 15, 4623–4630 (1995).
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Lee, S., Kolquist, K., Nichols, K. et al. The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. Nat Genet 17, 309–313 (1997). https://doi.org/10.1038/ng1197-309
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DOI: https://doi.org/10.1038/ng1197-309
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