Abstract
Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3′kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R− cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R− or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R− cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors.
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Acknowledgements
The authors wish to thank Dr Renato Baserga for supplying R− cells and Drs Michael Cox and Rob Kay for helpful discussions. This work was supported by funds from the Canadian Institutes for Health Research (to PHB Sorensen) and by funds from the Johal Program in Pediatric Oncology Basic and Translational Research at the BC Research Institute for Children's and Women's Health.
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Morrison, K., Tognon, C., Garnett, M. et al. ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation. Oncogene 21, 5684–5695 (2002). https://doi.org/10.1038/sj.onc.1205669
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DOI: https://doi.org/10.1038/sj.onc.1205669
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