STAT5 induces miR-21 expression in cutaneous T cell lymphoma
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Lise M. Lindahl1, Simon Fredholm2, Claudine Joseph2, Boye Schnack Nielsen3, Lars Jønson4, Andreas Willerslev-Olsen2, Maria Gluud2, Edda Blümel2, David L. Petersen2, Nina Sibbesen2, Tengpeng Hu2, Claudia Nastasi2, Thorbjørn Krejsgaard2, Ditte Jæhger2, Jenny L. Persson5, Nigel Mongan6, Mariusz A. Wasik7, Ivan V. Litvinov8, Denis Sasseville9, Sergei B. Koralov10, Charlotte M. Bonefeld2, Carsten Geisler2, Anders Woetmann2, Elisabeth Ralfkiaer11, Lars Iversen1, Niels Odum2
1Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
2Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
3Bioneer A/S, Hørsholm, Denmark
4Department of Molecular Medicine, Copenhagen University Hospital, Copenhagen, Denmark
5Clinical Research Center, Lund University, Malmö, Sweden
6School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom
7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
8Division of Dermatology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
9Division of Dermatology, McGill University Health Centre, Montréal, Quebec, Canada
10Department of Pathology, New York University School of Medicine, New York, NY, USA
11Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark
Lars Iversen, email: firstname.lastname@example.org
Niels Odum, email: email@example.com
Keywords: miR-21, in situ, STAT5, IL-2, cutaneous T-cell lymphoma (CTCL)
Received: March 23, 2016 Accepted: June 03, 2016 Published: June 18, 2016
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.
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