• Researcher Profile

    A. Thomas Look, MD

     
    A. Thomas Look, MD
     
    Professor of Pediatrics, Harvard Medical School

    Office phone: 617-632-5826
    Fax: 617-632-6989
    Email: thomas_look@dfci.harvard.edu

    Preferred contact method: email
     
     

    Research Department

    Pediatric Oncology

    Area of Research

    Genetic Models of Leukemogenesis and Neuroblastoma

    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Mayer 630
    Boston, MA 02215

    Biography

    Dr. Look received his MD in 1975 and residency training in pediatrics at the University of Michigan. He completed a fellowship in pediatric oncology at St. Jude Children's Research Hospital, where he trained in the molecular biology of cancer and eventually became chair of the Experimental Oncology Department. In 1999, he joined DFCI as vice chair for research in the Department of Pediatric Oncology.

    Recent Awards

    • ASPHO Frank A. Oski Memorial Lectureship Award, 2005
    • Member, Association of American Physicians

      , 2005
    • 2nd Annual Lecturer in Leukemia at The Hospital for Sick Children, Toronto, Canada, 2000
    • Second Annual Giulio J. D'Angio Lecturer, University of Pennsylvania Cancer Center, 1999
    • Award for Excellence in Pediatric Research, American Academy of Pediatrics, 1995

    Research

    Genetic Models of Leukemogenesis and Neuroblastoma

    We are using zebrafish, in combination with murine and cell culture systems, to dissect developmental pathways subverted in human cancer. Zebrafish have been shown to share conserved pathways of development and disease pathogenesis with humans, thus permitting the identification of novel genes that are activated (oncogenes) or inactivated (tumor suppressors) during malignant transformation. We are using transgenic strategies to generate conditional zebrafish models of leukemias and solid tumors.

    We have identified novel genes regulating myelopoiesis, and are currently studying their respective contributions to the molecular pathogenesis of myelodysplastic syndrome and acute myeloid leukemia. We are applying similar approaches to study peripheral sympathetic nervous system development and to identify tumor suppressors in childhood neuroblastoma. We have also isolated a tumor-prone, mutant p53 zebrafish to study pathways involving this key regulator of DNA repair, cell cycle regulation, and apoptosis. p53 is the most commonly mutated gene in human cancers, and our zebrafish model is allowing us to study its role in several types of cancer.

    Our most advanced zebrafish model involves a transgenic line that develops T cell acute lymphoblastic leukemia (T-ALL). We are using this model to conduct one of the first cancer-related vertebrate genetic modifier screens, which will allow us to identify enhancers and suppressors of T-ALL progression. Using in vitro genome-scale location analysis (GSLA), we are also identifying the direct targets of oncogenic transcription factors and validating candidate target genes utilizing short interfering RNA strategies in human T-ALL cell lines. Through the combined use of these approaches, we hope to uncover novel genes and targets for the development of small-molecule inhibitors as therapeutics.

    In addition, we are studying apoptotic pathways controlled by the Slug transcription factor. We have shown that, in developing blood cells, DNA damage and p53 induction leads to the activation of Slug, which itself is a direct repressor of puma, a pro-apoptotic BH3-only protein. Mice deficient in both genes survive irradiation doses that are lethal to mice lacking Slug alone. Thus, Slug provides a novel mechanism downstream of p53 to ensure cell survival, rescuing damaged hematopoietic progenitors from programmed cell death, and allowing restorative repopulation of blood cells after radiation and other insults that cause DNA damage.

    Select Publications

    • Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, Lin S, Prochownik E, Trede NS, Zon LI, Look AT. Myc-induced T cell leukemia in transgenic zebrafish. Science 2003;299:887-90.

    • Ferrando AA, Armstrong SA, Neuberg DS, Sallan SE, Silverman LB, Korsmeyer SJ, Look AT. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 2003;102:262-8.
    • Liu TX, Howlett NG, Deng M, Langenau DM, Hsu K, Rhodes J, Kanki JP, D'Andrea AD, Look AT. Knockdown of zebrafish Fancd2 causes developmental abnormalities via p53-dependent apoptosis. Dev Cell 2003;5:903-14.
    • Ferrando AA, Neuberg DS, Dodge RK, Paietta E, Larson RA, Wiernik PH, Rowe JM, Caligiuri MA, Bloomfield CD, Look AT. Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T cell acute lymphoblastic leukaemia. Lancet 2004;363:535-6.
    • Hsu K, Traver D, Kutok JL, Hagen A, Liu TX, Paw BH, Rhodes J, Berman J, Zon LI, Kanki JP, Look AT. The pu.1 promoter drives myeloid gene expression in zebrafish. Blood 2004;104:1291-7.
    • Weng AP, Ferrando AA, Lee W, Morris JP IV, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of Notch 1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
    • Berghmans S, Murphey RD, Wienholds E, Neuberg D, Kutok JL, Fletcher CD, Morris JP, Liu TX, Schulte-Merker S, Kanki JP, Plasterk R, Zon LI, Look AT. tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proc Natl Acad Sci U S A 2005;102:407-12.
    • Langenau DM, Feng H, Berghmans S,Kanki JP, Kutok JL, Look AT. Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2005:102:6068-73.
    • Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, Look AT. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 2005;123:641-53.

    Investigators

    • Kanki, John, PhD
    • George, Rani, MD, PhD

    Trainees

    • Grabher, Clemens, PhD
    • Gutierrez, Alejandro, MD
    • Heinrichs, Stefen, PhD
    • Jette, Cicely, PhD
    • Lee, Jeong-Soo, PhD
    • O'Neil, Jennifer, PhD
    • Rhodes, Jennifer, PhD
    • Sbrogna, Jennifer, PhD
    • Sidi, Samuel, PhD
    • Stewart, Rodney, PhD
    • Wu, Wen-Shu, PhD