DF/HCC Program Affiliation

Leukemia, Leader
Cancer Cell Biology

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Chromosomal 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.

Publications

• George RE, Attiyeh EF, Li S, Moreau LA, Neuberg D, Li C, Fox EA, Meyerson M, Diller L, Fortina P, Look AT, Maris JM.Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays.PLoS ONE 2007;2:e255.
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• Moreau LA, McGrady P, London WB, Shimada H, Cohn SL, Maris JM, Diller L, Look AT, George RE.Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children's Oncology Gro
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• Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, Mao M, Inaba T, Look AT.SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein.Mol Cell 1999 Sep;4(3):343-52.
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• Look AT.Oncogenic transcription factors in the human acute leukemias.Science 1997 Nov 7;278(5340):1059-64.
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• Inaba T, Inukai T, Yoshihara T, Seyschab H, Ashmun RA, Canman CE, Laken SJ, Kastan MB, Look AT.Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor.Nature 1996 Aug 8;382(6591):541-4.
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