1. ¹Molecular Oncology Laboratory, Faculty of Veterinary Medicine, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, Scotland
2. ²Lincoln's Inn Fields Laboratories, London Research Institute, London, UK
3. ³Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany

Correspondence: Professor JC Neil, Faculty of Veterinary Medicine, Institute of Comparative Medicine, University of Glasgow, Bearsden Road, Glasgow, Scotland G61 1QH, UK. E-mail: J.C.Neil@vet.gla.ac.uk

Received 19 February 2009; Revised 23 March 2009; Accepted 28 March 2009; Published online 18 May 2009.

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-RAS^V12, 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 p14^Arf, whereas only RUNX1-ETO induced senescence in p16^Ink4a-null cells. Correlation was noted between induction of p53, reactive oxygen species and phospho-p38, whereas p38^MAPK 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.