Title:
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An embryonic stem (ES) cell approach to study the role of WTl in haematopoiesis
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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.
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