Look, A. Thomas

We are interested in genetic models of leukemogenesis, particularly the highly conserved anti-apoptotic transcriptional pathway downstream of E2A-HLF, a chimeric oncoprotein activated by chromosomal translocation in childhood leukemia. Sequence homology between the HLF transcription factor and CES-2, a cell death specification protein in the nematode Caenorhabditis elegans, suggests that this pathway is not unique to developing B-lymphocytes, but has been evolutionarily conserved in diverse organisms. Recent evidence suggests that this pathway in mammalian cells involves Slug, a zinc-finger transcription factor that is highly related to CES-1, the gene located downstream of CES-2 in the worm. We are now focusing on the role of Slug in apoptosis, using mice with targeted disruption of the Slug gene. Our goal is to understand pathways of cell death specification in mammals --how they connect to the common machinery of programmed cell death and how they can be disrupted in malignant transformation.

A new area of research in the laboratory involves the use of the zebrafish genetic system to clarify developmental pathways subverted in human leukemias and solid tumors. The zebrafish animal model provides a powerful system for genetic analysis of vertebrate embryogenesis, organ development and disease. This model is unique within vertebrates in its capacity for 'forward' genetic analysis, through use of phenotype-driven mutational screens and readily accessible transparent embryos. These properties make the zebrafish an ideal system for gene discovery based on gene function, an advantage that should prove very useful in dissecting pathways of gene action during cell transformation.