title: CD164 identifies CD4+T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.
abstract: Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+T cells, CD164+and CD164-CD4+T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+compared with CD164-CD4+T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Bernice M
authors.initials: BM
authors.lastname: Benoit
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Jariwala
authors.affiliation: National Cancer Institute, Cancer and Inflammation Program, Frederick, MD, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: O'Connor
authors.affiliation: Division of Dermatology, Department of Medicine, Washington University, St. Louis, MO, USA.|The Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA.
authors.forename: Landon K
authors.initials: LK
authors.lastname: Oetjen
authors.affiliation: Division of Dermatology, Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Whelan
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Werth
authors.affiliation: Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.affiliation: Innate Pharma, Research and Drug Development, Marseille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Sicard
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Takeshita
authors.affiliation: National Cancer Institute, Cancer and Inflammation Program, Frederick, MD, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Division of Dermatology, Department of Medicine, Washington University, St. Louis, MO, USA.|Department of Anesthesiology, Washington University, St. Louis, MO, USA.|Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.|The Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA.
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1049 BRB, Philadelphia, PA, 19104, USA. mwysocka@mail.med.upenn.edu.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-3648-8429
authors.initials: M
authors.lastname: Wysocka
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry* / Q000276:immunology; D016022:Case-Control Studies; D051930:Endolyn / Q000032:analysis / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry* / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012751:Sezary Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C497898:CD164 protein, human; D051930:Endolyn; C457775:FCRL3 protein, human; D006609:High Mobility Group Proteins; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C558851:TOX protein, human
keywords: CD164; FCRL3; KIR3DL2; Sézary syndrome; Tox; miR-214