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RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress

Oncogene volume 28, pages 2502–2512 (2009)Cite this article

Abstract

A role for the RUNX genes in cancer fail-safe processes has been suggested by their induction of senescence-like growth arrest in primary murine fibroblasts and the failure of RAS-induced senescence in Runx2-deficient cells. We now show that RUNX1 induces senescence in human primary fibroblasts. High-affinity DNA binding is necessary but not sufficient, as shown by the functional attenuation of the truncated RUNX1/AML1a isoform and the TEL-RUNX1 fusion oncoprotein. However, a similar phenotype was potently induced by the RUNX1-ETO (AML1-ETO) oncoprotein, despite its dominant-negative potential. A detailed comparison of H-RASV12, RUNX1 and RUNX1-ETO senescent phenotypes showed that the RUNX effectors induce earlier growth stasis with only low levels of DNA damage signaling and a lack of chromatin condensation, a marker of irreversible growth arrest. In human fibroblasts, all effectors induced p53 in the absence of detectable p14Arf, whereas only RUNX1-ETO induced senescence in p16Ink4a-null cells. Correlation was noted between induction of p53, reactive oxygen species and phospho-p38, whereas p38MAPK inhibition rescued cell growth markedly. These findings indicate a role for replication-independent pathways in RUNX and RUNX1-ETO senescence, and show that the context-specific oncogenic activity of RUNX1 fusion proteins is mirrored in their distinctive interactions with fail-safe responses.

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Acknowledgements

Primary support for this work was provided by Cancer Research UK and the Leukemia Research Fund. We thank Janice Rowe for excellent technical assistance and Scott Hiebert (Vanderbilt University) for generous supply of reagents and useful discussions.

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Authors and Affiliations

  1. Molecular Oncology Laboratory, Faculty of Veterinary Medicine, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, Scotland

    K Wolyniec, S Wotton, A Kilbey, A Jenkins, A Terry, E Cameron & J C Neil

  2. Lincoln's Inn Fields Laboratories, London Research Institute, London, UK

    G Peters

  3. Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany

    C Stocking

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  1. K Wolyniec
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  2. S Wotton
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  3. A Kilbey
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  8. E Cameron
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  9. J C Neil
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Correspondence to J C Neil.

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Wolyniec, K., Wotton, S., Kilbey, A. et al. RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress. Oncogene 28, 2502–2512 (2009). https://doi.org/10.1038/onc.2009.101

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