CD73 FUNCTION DURING LYMPHOCYTE DEVELOPMENT

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Research Plans Ecto-5'-nucleotidase (5'-NT, CD73) is a purine salvage enzyme expressed on the surface of normal and malignant human lymphocytes. 5'-NT has signal transducing capabilities as demonstrated by the ability of 5'-NT antibodies to cause human lymphocyte proliferation. Since high expression of 5'-NT is associated with a poor prognosis in acute lymphoblastic leukemia, it is possible that this molecule transmits signals that promote the uncontrolled proliferation of these cells. 5'-NT expression appears to be highly regulated during lymphocyte development, increasing with maturation of both T and B cells. The goals of the proposed research are to determine the importance of regulated expression of 5'-NT in lymphocyte differentiation and will be examined by inappropriately overexpressing 5'-NT in early T B cells and by ablating expression in mature cells. 5'-NT will be overexpressed in either immature murine thymocytes or B cells by expressing human 5'-NT in transgenic mice under the control of the lck promoter or IgH enhancer, respectively. 5'-NT will be deleted in mature T and B cells by making knockout mice. The effect of such inappropriate expression on the histology of the thymus, spleen, bone marrow and lymph nodes in the mature mouse, and on the phenotype of T and B cells in these lymphoid organs, will be examined. The ontogeny of T and B cell development in the fetal thymus, spleen, and liver, and the function of mature T and B cells will be examined. Mice will be observed for the development of lymphoid tumors, which will be characterized if they occur. The proposed work will not only reveal new insights into the importance of regulated expression of 5'-NT during lymphocyte differentiation, but will also allow the applicant to develop skills in transgenic technology and contribute toward her development as an independent investigator.