Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Divergent Ewing's sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells

Oncogene volume 18, pages 5506–5513 (1999)Cite this article

Abstract

Ewing's sarcomas express chimeric transcription factors resulting from a fusion of the amino terminus of the EWS gene to the carboxyl terminus of one of five ETS proteins. While the majority of tumors express EWS/FLI1 fusions, some Ewing's tumors contain variant chimeras such as EWS/ETV1 that have divergent ETS DNA-binding domains. In spite of their structural differences, both EWS/ETS fusions up regulate EAT-2, a previously described EWS/FLI1 target gene. In contrast to EWS/FLI1, NIH3T3 cells expressing EWS/ETV1 cannot form colonies in soft agar though coexpression of a dominant negative truncated ETV1 construct attenuates EWS/FLI1 mediated anchorage independent growth. When EWS/ETV1 or EWS/FLI1 expressing NIH3T3 cells are injected into SCID mice, tumors form more often and faster than with NIH-3T3 cells with empty vector controls. The tumorigenic potency of each EWS/ETS fusion is linked to its C-terminal structure, with the FLI1 C-terminus confering a greater tumorigenic potential than the corresponding ETV1 domain. The resulting EWS/ETV1 and EWS/FLI1 tumors closely resemble each other at both a macroscopic and a microscopic level. These tumors differ greatly from tumors formed by NIH3T3 cells expressing activated RAS. These data indicate that in spite of their structural differences, EWS/ETV1 and EWS/FLI1 promote oncogenesis via similar biologic pathways.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Auvinen M, Laine A, Paasinen-Sohns A, Kangas A, Kangas L, Saksela O, Andersson LC and Holtta E. . 1997 Cancer Res. 57: 3016–3025.

  • Basuyaux JP, Ferreira E, Stehlin D and Buttice G. . 1997 J. Biol. Chem. 272: 26188–26195.

  • Bernstein SC and Weinberg RA. . 1985 Proc. Natl. Acad. Sci. USA 82: 1726–1730.

  • Bertolotti A, Lutz Y, Heard DJ, Chambon P and Tora L. . 1996 EMBO J. 15: 5022–5031.

  • Bertolotti A, Melot T, Acker J, Vigneron M, Delattre O and Tora L. . 1998 Mol. Cell. Biol. 18: 1489–1497.

  • Braun BS, Frieden R, Lessnick SL, May WA and Denny CT. . 1995 Mol. Cell. Biol. 15: 4623–4630.

  • Cardinali M, Kratochvil FJ, Ensley JF, Robbins KC and Yeudall WA. . 1997 Mol. Carcinogen. 18: 78–88.

  • Conrad KE, Oberwetter JM, Vaillancourt R, Johnson GL and Gutierrez-Hartman A. . 1994 Mol. Cell. Biol. 14: 1553–1565.

  • de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, Gerald WL, Jhanwar SC, Argani P, Antonescu CR, Pardo-Mindan FJ, Ginsberg J, Womer R, Lawlor ER, Wunder J, Andrulis I, Sorenson PH, Barr FG and Ladanyi M. . 1998 J. Clin. Oncol. 16: 1248–1255.

  • de Launoit Y, Baert J, Chotteau A, Monte D, Defossez P, Coutte L, Pelczar H and Leenders F. . 1997 Biochem. Mol. Med. 61: 127–135.

  • del Paso L, Hernandez-Alcoceb R, Embade N, Carnero A, Esteve P, Paje C and Lacal JC. . 1997 Oncogene 15: 3047–3057.

  • Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ, Aurias A and Thomas G. . 1994 New Eng. J. Med. 331: 294–299.

  • Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Heinrich K, Houbert I, de Jong P, Rouleau G, Aurias A and Thomas G. . 1992 Nature 359: 162–165.

  • Denny CT. . 1996 Cancer Investigation 14: 83–88.

  • Downing JR and Look AT. . 1996 Can. Treatment Res. 84: 73–92.

  • Fletcher JA. . 1998 J. Clin. Oncol. 16: 1241–1242.

  • Fridman R, Sweeney TM, Zain M, Martin GR and Kleinman HK. . 1992 Int. J. Cancer 51: 740–744.

  • Giovannini M, Biegel JA, Serra M, Wang JY, Wei YH, Nycum L, Emanuel BS and Evans GA. . 1994 J. Clin. Invest. 94: 489–496.

  • Janknecht R. . 1996 Mol. Cell. Biol. 16: 1550–1556.

  • Jeon IS, Davis JN, Braun BS, Sublett JE, Roussel MF, Denny CT and Shapiro DN. . 1995 Oncogene 10: 1229–1234.

  • Kaneko Y, Yoshida K, Handa M, Toyoda Y, Nishihira Y, Tanaka Y, Sasaki Y, Ishida S, Higashino F and Fujinaga K. . 1996 Genes Chrom. Cancer 15: 115–121.

  • Kovar H, Aryee DN, Jug G, Henockl C, Schemper M, Delattre O, Thomas G and Gadner H. . 1996 Cell Growth Diff. 7: 429–437.

  • Kovar H. . 1998 Sarcoma 2: 3–17.

  • Krogerman P, Sy MS and Culp LA. . 1997 Oncogene 15: 1407–1416.

  • Kurzepa H, Kyriazis AP and Lang DR. . 1984 J. Environ. Path. Toxicol. Oncol. 5: 131–138.

  • Langer SJ, Bortner DM, Roussel MF, Sherr CJ and Ostrowski MC. . 1992 Mol. Cell. Biol. 12: 5355–5362.

  • Lo SC and Liotta LA. . 1985 Am. J. Path. 118: 7–13.

  • Lugo TG and Witte ON. . 1989 Mol. Cell. Biol. 9: 1263–1270.

  • May WA, Arvand A, Thompson AD, Braun BS, Wright M and Denny CT. . 1997 Nature Genetics 17: 495–497.

  • May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC, Delattre O, Zucman J, Thomas G and Denny CT. . 1993a Proc. Natl. Acad. Sci. USA 90: 5752–5756.

  • May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC, Lunsford LB, Hromas R and Denny CT. . 1993b Mol. Cell. Biol. 13: 7393–7398.

  • McNagny KM, Sieweke MH, Doderlein G, Graf T and Nerlov C. . 1998 EMBO 13: 3669–3680.

  • Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H and Delattre O. . 1997 Oncogene 14: 1159–1164.

  • Rabbitts TH. . 1994 Nature 372: 143–149.

  • Rao VN, Ohno T, Prasad DDK, Bhattacharya G and Reddy ESP. . 1993 Oncogene 8: 2167–2173.

  • Rowley JD. . 1993 Leukemia 8: (Suppl 1) S1–S6.

  • Rubin H. . 1984 J. Nat. Can. Inst. 72: 375–381.

  • Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarlo MG, Oettgen H, De Vries JE, Aversa G and Terhorst C. . 1998 Nature 395: 462–469.

  • Sorenson PH, Lessnick S, Lopes-Terrada D, Liu XF, Triche TJ and Denny CT. . 1994 Nature Genetics 6: 146–151.

  • Sorenson PH and Triche TJ. . 1996 Seminars in Cancer Biology 7: 3–14.

  • Thompson AD, Braun BS, Arvand A, Stewart SD, May WA, Chen E, Korenberg J and Denny CT. . 1996 Oncogene 13: 2649–2658.

  • Urano F, Umezawa A, Hong W, Kikuchi H and Hata JI. . 1996 Biochim. Biophys. Res. Com. 219: 608–612.

  • Wasylyk C, Maira S, Sobieszczuk P and Wasylyk B. . 1994 Oncogene 9: 3665–3673.

  • Zinszner H, Albalat R and Ron D. . 1994 Genes Dev. 8: 2513–2526.

  • Zoubek A, Dockhorn-Dworniczak B, Delattre O, Christiansen H, Niggli F, Gatterer-Menz I, Smith TL, Jurgens H, Gadner H and Kovar H. . 1996 J. Clin. Oncol. 14: 1245–1251.

  • Zucman J, Melot T, Desmaze C, Ghysdael J, Plougastel B, Peter M, Zucker JM, Triche TJ, Sheer D, Turc-Carel C, Ambros P, Combaret V, Lenoir G, Aurias A, Thomas G and Delattre O. . 1993 EMBO J. 12: 4481–4487.

Download references

Acknowledgements

This work was funded by a grant from the American Cancer Society (DB-72) and the National Cancer Institute (CA32737). ADT is supported by NIH grant GM08042, MAT by the Lymphoma Research Foundation of America and AA by training grant CA09056. The authors wish to gratefully acknowledge the following individuals for assistance in building, sequencing, and testing constructs: Emily Chen, Akemi Yamaguchi, Steven Heber and Talin Hartunians. We would like to thank Elliot Landaw for performing statistical analysis of this data, Robin Simpkins for tissue processing and Harvey Herschman and Linda Baum for critical review of this manuscript.

Author information

Authors and Affiliations

  1. Molecular Biology Institute, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, LA, USA

    Andrew D Thompson, Michael A Teitell & Christopher T Denny

  2. Jonsson Comprehensive Cancer, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, LA, USA

    Andrew D Thompson, Michael A Teitell, Afsane Arvand & Christopher T Denny

  3. Department of Pathology and Laboratory Medicine, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, LA, USA

    Michael A Teitell & Afsane Arvand

  4. Department of Pediatrics, Gwynne Hazen Cherry Memorial Labs, University of California at Los Angeles, LA, USA

    Christopher T Denny

  5. Department of Pathology, Children's Hospital Los Angeles and University of Southern California, California, CA, USA

    Michael A Teitell

Authors
  1. Andrew D Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A Teitell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Afsane Arvand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher T Denny
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thompson, A., Teitell, M., Arvand, A. et al. Divergent Ewing's sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells. Oncogene 18, 5506–5513 (1999). https://doi.org/10.1038/sj.onc.1202928

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202928

Keywords

This article is cited by

Search

Advanced search

Quick links