SSA Investigating the regulatory crosstalk between Ras signalling and the transcription factor Ebf1

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The EBF family of DNA-binding proteins play roles in various developmental processes, their inactivation blocks normal development, which often results in human cancer. The most-studied family member, Ebf1 is required for B lymphocyte development and its tumour suppressor role in acute lymphoid leukaemia has been proven by animal experiments and by genetic studies. Using a conditional knockout allele, our group has shown that Ebf1 is required for replication and survival of B cells. Genetic evidence suggests that Ebf1 is expressed in human lung tissue, but its role in this organ is entirely unknown. Expression significantly decreases in a set of non-small-cell lung carcinomas, and these cells would provide naturally occurring loss of function tools for mechanistic studies. Ebf1 has been shown to alter either the chromatin state or transcription of its target loci during B lymphocyte development, but the role of Ebf1 in lung tissue has never been addressed before.The aim of this project is to study the potential of Ebf1 as an important regulator of lung development and whether the synergism between the pathways governed by Ebf1 and RAS, which is a characteristic property of developing B cells, would be relevant in lung tissue as well. This will be achieved by first using a cellular approach to manipulate the two pathways in in vitro cultured primary cells and transformed cell lines, followed by studies in a unique animal model that simultaneously activates KRAS and inactivates the Ebf1 gene.