The University of Texas MD Anderson Cancer Center
Department of Epigenetics and Molecular Carcinogenesis
My research program focuses on investigations of the molecular pathways that regulate normal T-lymphocyte development and, conversely, the aberrant molecular pathways that result in lymphoma development. With regard to normal T-cell development, we are particularly interested in elucidating the interdependent, inductive interactions that occur between immature thymocytes and thymic epithelial cells (TECs) during the intrathymic maturation of both cell types. Ongoing studies involve identification of cortical and medullary TEC subsets and evaluation of their capacity to promote thymocyte differentiation. Using various transgenic and knock-out mouse models in which T-lymphocyte development is blocked at specific stages of maturation, we recently identified and characterized previously unrecognized TEC subsets and established their lineage relationships. Furthermore, we demonstrated that normal cortical TEC development requires interactions with early lymphocyte precursors that have undergone exclusive commitment to the T-cell lineage. The current objectives are to elucidate the cellular and molecular pathways that mediate the cross-talk that is essential for proper development of both thymocytes and TECs.
Neoplastic transformation of thymocytes results in the development of thymic lymphomas. We work with an experimental model in which murine thymic lymphomas are induced by a single injection of the carcinogen N-methyl-N-nitrosourea (MNU). Our earlier studies showed that the AKR/J mouse strain is more susceptible to MNU-induced lymphomagenesis than other common inbred mouse strains. A major goal of this research project has been to identify and characterize the genes that are responsible for the enhanced susceptibility of the AKR/J strain. Using molecular genetic approaches such as conventional mapping and deletion analyses, we recently localized a novel lymphoma susceptibility gene to a 150 kb interval on murine chromosome 7. A candidate gene designated eed was found to map within this interval. Interestingly, eed belongs to the Polycomb group gene family. The members of this gene family function as long-term transcriptional repressors. Our working hypothesis is that a defect in the regulatory or coding region of the eed locus prevents the transcriptional depression of genes that promote lymphoma progression, thereby conferring greater susceptibility to lymphoma development. Current studies focus on identifying the molecular mechanisms by which eed acts as a tumor suppressor/susceptibility gene in regulating lymphoma development.
Education & Training
PhD, The University of Texas at Austin, 1970
Thymus Development and Homeostasis