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STAT5 induces miR-21 expression in cutaneous T cell lymphoma

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

Original languageEnglish
JournalOncotarget
Volume7
Issue number29
Pages (from-to)45730-45744
Number of pages15
ISSN1949-2553
DOIs
Publication statusPublished - 19 Jul 2016

ID: 49651676