Gene expression abnormalities in mycosis

描述(申请人提供)：真菌样肉芽肿(MF)是一种皮肤归巢、记忆、CD4+T细胞的恶性肿瘤。这是一种具有不同临床表现和慢性进行性病程的疾病。随着疾病的发展到晚期，肿瘤负担增加，更广泛的皮肤受累，导致全身红皮病或全身红肿。当异常的T细胞进入血液循环时，就被称为塞萨里病。为了更好地了解这种复杂的皮肤恶性肿瘤，我们采取了分子方法，最初的研究集中在Sezary患者的T细胞上，因为外周血中有丰富的肿瘤细胞。通过对Sezary病患者外周血单个核细胞(PBMC)的分析，我们发现Sezary病患者肿瘤T细胞中存在严重的细胞因子基因表达缺陷。为了进一步研究基因表达异常的病因学，我们采用了基因表达谱方法，假设正常T细胞和Sezary T细胞之间存在广泛的基因表达差异，这解释了它们的分子和临床表型。利用高密度Affymetrix寡核苷酸微阵列对正常人和MF(Sezary)患者纯化的T细胞的总RNA进行分析，我们发现了Sezary T细胞中高表达30倍以上的基因，以及在正常记忆T细胞中优先表达缺失的基因。在这个提案中，我们将关注一组在MF-Sezary T细胞中高表达的基因，因为这些基因可能会对这种疾病有深入的了解，并可能导致改善诊断。这项资助的目的是：1.验证MF患者的MF-Sezary基因。2.确定这些异常基因的表达首先在受影响组织中出现的疾病阶段。3.研究这些基因在体外和体内的表达是否发生改变。

DESCRIPTION (provided by applicant): 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.