A. T. Look, MD
Professor, Department of Pediatrics, Harvard Medical School
Vice-Chair for Research, Pediatric Oncology, Dana-Farber Cancer Institute
DF/HCC Program AffiliationLeukemia, Leader
Cancer Cell Biology
DF/HCC AssociationsMember, Center Scientific Council
Research AbstractChromosomal translocations in the human acute leukemias often rearrange the regulatory and coding regions of genes encoding developmentally regulated transcription factors. In broadest terms, my laboratory is interested in the consequences of these molecular events, especially how the resulting aberrant proteins interfere with regulatory networks that control the growth, differentiation, and survival of normal blood cell precursors. Our primary focus is on a fusion oncoprotein that combines the key elements of two developmentally important transcription factors and induces a B-cell precursor subtype of acute lymphoblastic leukemia in older children and adolescents. Designated E2A-HLF, this chimeric protein prolongs the survival of IL-3-dependent murine pro-B cells after withdrawal of the growth factor, indicating that it disrupts a signaling pathway normally responsible for programmed cell death, so that the cells accumulate as leukemic lymphoblasts. 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.
A new area of research within the laboratory involves the use of a 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.