Details

Autor(en) / Beteiligte

• Lindahl, Lise M
• Fredholm, Simon
• Joseph, Claudine
• Nielsen, Boye Schnack
• Jønson, Lars
• Willerslev-Olsen, Andreas
• Gluud, Maria
• Blümel, Edda
• Petersen, David L
• Sibbesen, Nina
• Hu, Tengpeng
• Nastasi, Claudia
• Krejsgaard, Thorbjørn
• Jæhger, Ditte
• Persson, Jenny L
• Mongan, Nigel
• Wasik, Mariusz A
• Litvinov, Ivan V
• Sasseville, Denis
• Koralov, Sergei B
• Bonefeld, Charlotte M
• Geisler, Carsten
• Woetmann, Anders
• Ralfkiaer, Elisabeth
• Iversen, Lars
• Odum, Niels

Titel

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Ist Teil von

• Oncotarget, 2016-07, Vol.7 (29), p.45730-45744

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.