title: STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
abstract: In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR-21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2-induced miR-21 expression in cytokine-independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lise M
authors.initials: LM
authors.lastname: Lindahl
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Fredholm
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claudine
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Bioneer A/S, Hørsholm, Denmark.
authors.forename: Boye Schnack
authors.initials: BS
authors.lastname: Nielsen
authors.affiliation: Department of Molecular Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Willerslev-Olsen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Gluud
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Edda
authors.initials: E
authors.lastname: Blümel
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: David L
authors.initials: DL
authors.lastname: Petersen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Sibbesen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tengpeng
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nastasi
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Krejsgaard
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ditte
authors.initials: D
authors.lastname: Jæhger
authors.affiliation: Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Persson
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mongan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: Division of Dermatology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.affiliation: Division of Dermatology, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Sasseville
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiaer
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
mesh_terms: D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050799:STAT5 Transcription Factor
keywords: IL-2; STAT5; cutaneous T-cell lymphoma (CTCL); in situ; miR-21