Mycosis fungoides is the most common form of Cutaneous T Cell Lymphoma, which is in turn the most common adult non-Hodgkin's T cell lymphoma. When the disease is correctly diagnosed in its earliest stages, several treatments are available to arrest disease progression. However, when the diagnosis is made in later stages (e.g.,, > Stage II), long-term survival is unusual. Current treatments for CTCL are effective primarily when disease is limited clinically to skin; therapies for disease that clinically involves lymph node, peripheral blood, and other organs is largely palliative. There are large deficiencies in our ability to diagnose and treat this non-Hodgkins lymphoma. Moreover, our understanding of the biology of this disease is at best primitive. In the last decade, our understanding of how memory T cells mediate immunosurveillance in different tissues has grown exponentially. Memory T cells that home to skin utilize specific cell surface molecules to exit blood into skin, including CLA, CCR4, and LFA-1. This occurs constitutively, as normal skin contains many such cells, but is greatly facilitated by inflammation, which up-regulates the ligands of the above molecules. Our preliminary data and that of others compel us to state the hypothesis that CTCL is a malignancy of CD4+ skin homing memory T cells. Against this background, we propose the following Specific Aims. To improve our ability to diagnose and treat CTCL, we propose to fully characterize, both functionally and phenotypically, the molecules on MF T cells that are involved with T cell trafficking. We propose that CTCL that involves skin only will express high levels of CCR4 and CCR10 and relatively little CCR7 an L selectin. Conversely, T cells in CTCL that involves lymph nodes will express L selectin, CCR7, and LFA-1 the trinity of homing molecules required for entry into lymph node from blood. Finally, we will test the hypothesis that leukemic CTCL cells do not respond well to skin derived chemokines normally involved in skin homing. In a second specific aim, we seek to generate new hypotheses about the biology of CTCL, by using whole genome microarray approaches to human CTCL cells and normal T cells. Taken together, we believe that these studies will improve the accuracy of both diagnosis and prognosis in this disease.
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