The Wilms' tumour suppressor 1 gene (WT]) is a multi-isoform and highly conserved transcription factor that has been implicated in the development of numerous malignancies, including leukaemia. Genetic evidence shows that 15-20% of acute leukaemias display inactivating mutations in WT], whilst the majority of the remainder strongly overexpress WT1, suggesting a role for the gene in normal haematopoiesis. Due to midgestation lethality of the Wtl null mouse of heart failure, precluding detailed analysis of the effects of a loss ofWtl function on haematopoiesis in vivo, this study utilizes an embryonic stem (ES) cell approach. Wtl null ES cells were compared to wild type ES cells during embryoid body (EB) differentiation in a classical loss of function analysis, and their ability to generate haematopoietic lineages was assessed. Wtl null ES cells were severely compromised in their ability to form haematopoietic lineages, but were not compromised in their generation of the in vitro haemangioblast. A novel role for Wtl in the protection against apoptosis ofhaematopoietic progenitors is proposed, revealed by increased apoptotic activity in Wtl null ES cell derived haematopoietic cells. Vascular endothelial growth factor (Vegf-a) administration reduces Wtl null apoptotic activity and rescues the Wtl null haematopoietic impairment. Vegf-a is a putative Wtl target gene, according to previous studies in murine kidneys and heart. This led to the hypothesis that Vegf-a signalling downstream ofWtl transcriptional transactivation mediates the protection against apoptosis during haematopoietic development.