The long term goal of this research is to determine what factors regulate expression of the glucocorticoid receptor (GR) protein, how this causes hormone-mediated apoptosis in leukemic cells, and how new targeted, rational, chemotherapeutic modalities can be developed to treat T-cell acute lymphoblastic leukemia (ALL). The central hypothesis of this research proposal is that regulated and selective GR promoter utilization is important in physiological and pathological conditions, and that this can be exploited in developing treatment modalities in the future.
The specific aims of this proposal are to: 1) analyze the cell cycle (S phase) specific regulation of GR gene expression including the: role that the transcription factor YY1 plays in regulating GR gene transcription; possible involvement of nuclear matrix association in this process; identification of the GR promoter sequences that regulate cell cycle dependent expression; 2) resolve the contribution of differential GR promoter utilization in cell type-and cell cycle- dependent expression of the GR gene, focusing on the: possible role for matrix localization of the promoter sites; cis-acting and trans-acting factors that control preferential GR promoter utilization; and 3) determine the mechanism for coordinate up-regulation of GR and c-jun gene expression in T-cell ALL, which is responsible for glucocorticoid- mediated apoptosis, by: mapping the element(s) in the c-jun promoter responsible for hormone-induced activation; isolating the human T-cell specific GR promoter and identifying the GR promoter element(s) that are activated by hormone. These comprehensive, yet focused, studies will give definitive answers about three important, yet poorly understood, aspects of GR action: the cell-cycle specific expression of the GR; selective GR receptor promoter utilization; and, the mechanism by which GR up-regulation during hormone treatment induces apoptosis in T-cell lymphoblasts. Future extensions of this research will be to determine if promoter silencing plays a role in the conversion of T-lymphoblasts from the steroid-sensitive to the hormone-resistant phenotype. An eventual goal will be to analyze GR promoter utilization and structure in glucocorticoid-resistant, human T-lymphoblasts from acute lymphoblastic leukemia patients at diagnosis, during remission, and at relapse. Ultimately, we wish to translate these basic science results into clinical applications regarding a rationale approach to combined chemotherapy in T-cell ALL.
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