Mycosis fungoides (MF) is a cutaneous malignancy of skin homing, memory, CD4+ T cells.  This is a disease with diverse clinical presentations and a chronic progressive course.  As the disease progresses to later stages, there is increasing tumor burden with more extensive skin involvement, causing generalized erythroderma or redness with systemic involvement.  When the abnormal T cells enter the circulation, it is known as Sezary disease.  To gain a better understanding of this complex cutaneous malignancy, we have taken a molecular approach, initially focusing our studies on T cells from Sezary patients since there are abundant tumor cells in the peripheral blood.  From analysis of peripheral blood mononuclear cells (PBMC) from patients with Sezary disease, we have identified profound cytokine gene expression defects in tumor T cells in patients with Sezary disease.  To further study the etiology for gene expression abnormalities, we have taken a gene expression profiling approach, hypothesizing that there are extensive gene expression differences between normal T cells and Sezary T cells that account for their molecular and clinical phenotype.  Using high-density Affymetrix oligonucleotide microarrary profiling of total RNA from purified T cells from normal individuals and from MF (Sezary) patients, we have discovered genes that are highly expressed by greater than 30-fold in Sezary T cells, as well as genes that are preferentially loss that are expressed in normal memory T cells.  In this proposal, we will focus on a set of genes that are highly expressed in MF-Sezary T cells, as these may yield insight into this disease and may lead to improve diagnosis.  The aim of this grant is: 1.  To validate the MF-Sezary genes in MF patients.  2.  To determine the stage of disease that the expression of these abnormal genes first become detectable in affected tissue.  3.  To study whether the expression of these genes are altered by therapy in vitro and in vivo. [ unreadable] [unreadable] [unreadable] [unreadable]