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Downregulation of Fas Gene Expression in Sézary Syndrome Is Associated with Promoter Hypermethylation
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Downregulation of Fas Gene Expression in Sézary Syndrome Is Associated with Promoter Hypermethylation
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Journal Article
Downregulation of Fas Gene Expression in Sézary Syndrome Is Associated with Promoter Hypermethylation
2010
Overview
Sézary Syndrome (SS) is an aggressive leukemic variant of primary cutaneous T-cell lymphoma characterized by the presence of tumor or Sézary cells that generally display a mature memory T-cell immunophenotype. Sézary cells proliferate poorly and therefore their accumulation may be due to defective T-cell homeostasis involving resistance to apoptosis. In this study, we analyzed Fas expression in CD4+ lymphocytes at the mRNA and protein levels in a large cohort of SS patients as compared with healthy controls. Fas mRNA expression was dysregulated in 34/47 patients, with significant under- and overexpression of Fas mRNA detected in 21 and 13 patients respectively (P<0.01). Examination of cell-surface Fas expression showed correlation with the observed downregulation of mRNA in CD4+ T cells. Mutational analysis demonstrated that functional FAS gene mutations are rare. Moreover, 16 SS patients who showed significant under-expression of Fas mRNA also showed significant positional hypermethylation within the FAS CpG island, which was not present in healthy controls or SS patients determined to have normal or overexpression of Fas mRNA. These data demonstrate that dysregulation of Fas expression is a common feature of SS, and provide a rationale for targeted therapies to restore the extrinsic Fas-dependent apoptotic pathway in this malignancy.
Publisher
Elsevier Inc,Nature Publishing Group,Elsevier Limited
Subject
/ Biological and medical sciences
/ CD4-Positive T-Lymphocytes - physiology
/ Down-Regulation - physiology
/ Gene Expression Regulation, Neoplastic
/ Hematologic and hematopoietic diseases
/ Humans
/ Immunologic Memory - physiology
/ Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
/ Polymorphism, Single-Stranded Conformational
