Abstract
EWS–WT1 is a chimeric transcription factor resulting from fusion of the N-terminal domain of the Ewing sarcoma gene EWS to the three C-terminal zinc fingers of the Wilms tumor suppressor WT1. This translocation underlies desmoplastic small round cell tumor (DSRCT), which is noted for the abundance of reactive stroma surrounding islets of tumor cells, suggestive of paracrine signals contributing to tumor cell proliferation. Hybridization to high-density oligonucleotide microarrays can be used to identify targets of EWS–WT1. Expression of EWS–WT1 from a tetracycline-regulated promoter leads to the induction of growth-associated genes, of which the most remarkable is the beta-chain of the interleukin-2/15 receptor (IL-2/15Rβ). Potent transcriptional activation by the chimeric protein maps to two bindings sites within the IL-2/15Rβ promoter. Analysis of primary DSRCT tumor specimens demonstrates high levels of IL-2/15Rβ within the tumor cells, along with expression of IL-2 and IL-15 by the abundant hyperplastic endothelial cells within the reactive stroma. Activation of this cytokine signaling pathway is consistent with the nuclear localization of its downstream effectors, phosphorylated STAT3 and STAT5. These observations suggest that the transcriptional induction of a cytokine receptor by a tumor-associated translocation product enables a proliferative response of epithelial cancer cells to ligands secreted by the surrounding stroma.
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Acknowledgements
We thank Shiv Pillai and members of the Haber laboratory for helpful discussions and critical review of the manuscript, and Muzaffar Akram for technical assistance. This work was supported by National Institutes of Health grant CA58596 (DA Haber), CA68273 (WL Gerald) and the MGH Medical Discovery Fund (SB Lee).
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Wong, J., Lee, S., Bell, M. et al. Induction of the interleukin-2/15 receptor β-chain by the EWS–WT1 translocation product. Oncogene 21, 2009–2019 (2002). https://doi.org/10.1038/sj.onc.1205262
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DOI: https://doi.org/10.1038/sj.onc.1205262
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