Cellular senescence is an end point of a signal transduction programme leading to irreversible cell cycle arresst accompanied by characteristic alterations to cell morphology, biochemical properties and gene expression profile. This phenotype can be triggered by a variety of stimuli including telomere shortening, DNA damage or activated oncogenes. Senescence is now recognised as a tumour suppressor mechanism mediated by p53 and pRB pathways which act to prevent the proliferatio of cells that are at risk of tumourigenic transformation. RUNX1 is a transcription factor essential for definitive hematopoiesis and is frequently targeted in human leukaemias by chromosomal rearrangements. RUNX1 has been also demonstrated to act as a dominant oncogene in mice and the ectopic expression of RUNX1 in murine embryonic fibroblasts has been shown to cause senescence. The central aim of this study was to investigate the mechanism of senescence induction by RUNX1 and its fusion derived leukaemogenic oncoproteins in primary fibroblasts. My work showed that RUNX1 induces a strong senescence-like response in murine and human primary fibroblasts that requires intact DNA binding, CBFB interaction and C-terminal transcriptional activation/repression domains. However, surprising differences were found between the major RUNX1 fusion oncoprotein derivatives. The N-terminal fusion protein TEL-RUNX1 fails to induce senescence despite retention of a virtually full-lenght RUNX1 moiety, while the senescence-inducing potential is exaggerated in the truncated C-terminal fusion protein RUNX1-ETO (AML1-ETO). The potential to drive senescence is retained by the deletion mutant RUNX1-ETO469 which lacks critical corepressor binding sites suggesting that the repression of target genes may be a primary mechanism implicated in RUNX1-ETO induced senescence. Interestingly, CBFB-MYH11 fusion oncoprotein that affects RUNX1 indirectly by targeting CBFB cn also induce senescence when ectopically expressed in human primary cells. The RUNX1 and RUNX1-ETO induced senescent phenotypes differ from archetypal H-Ras [superscript v12] as arrest occurs without a preliminary phase of proliferation and the arrested cells lack prominent foci of DNA strand breaks and chromatin condensation. Notably however, RUNX1 and RUNX1-ETO display differences in their potency and the extent of engagement of p53 and Rb effector pathways. RUNX1-ETO is highly dependent on p53 function and unlike RUNX1 drives senescence in cells lacking intact p16Ink4a. RUNX1-ETO appears to exert its unique effects through potent induction of reactive oxygen species and p38MAPK phosphorylation. These findings illustrate the heterogeneous manifestations of senescence-like growth arrest and elucidate the distinctive biology and oncogenic properies of RUNX1 and its fusion derivatives.