title: Promoter-Specific Hypomethylation Is Associated with Overexpression of PLS3, GATA6, and TWIST1 in the Sezary Syndrome.
abstract: The Sézary Syndrome (SS) is an aggressive CD4+ leukemic variant of cutaneous T-cell lymphoma. Epigenetic modification of cancer cell genome is often linked to the expression of important cancer-related genes. Here we addressed the hypothesis that, in SS, DNA hypomethylation is involved in upregulation of PLS3, GATA6, and TWIST1, genes that are undetected in normal lymphocytes. Pyrosequencing analysis of CpG rich regions, and CpG dinucleotides within the 5' regulatory regions, confirmed hypomethylation of all three genes in SS, compared with controls. We then studied how methylation regulates PLS3 transcription in vitro using PLS3-negative (Jurkat) and PLS3-positive (HT-1080) cell lines. Treatment with the hypomethylating agent 5-azacytidine induced PLS3 expression in Jurkat cells and in vitro methylation of the cloned PLS3 promoter suppressed luciferase expression in HT-1080 cells. In conclusion, we show that promoter hypomethylation is associated with PLS3, GATA6, and TWIST1 overexpression in SS CD4+ T cells and that methylation can regulate PLS3 expression in vitro. The mechanisms of DNA hypomethylation in vivo and the functional role of PLS3, TWIST1, and GATA6 in SS are being investigated.
authors: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA. Electronic address: hkwong@uams.edu.
authors: Henry K
authors: HK
authors: Wong
authors: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; These authors contributed equally to this work.
authors: Heather
authors: H
authors: Gibson
authors: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors: Timothy
authors: T
authors: Hake
authors: The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Susan
authors: S
authors: Geyer
authors: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Julie
authors: J
authors: Frederickson
authors: The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors: Guido
authors: G
authors: Marcucci
authors: The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors: Michael A
authors: MA
authors: Caligiuri
authors: The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. Electronic address: Pierluigi.Porcu@osumc.edu.
authors: Pierluigi
authors: P
authors: Porcu
authors: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. Electronic address: Anjali.Mishra@osumc.edu.
authors: Anjali
authors: A
authors: Mishra
mesh_terms: D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012751:Sezary Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C026742:plastin; D001374:Azacitidine