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STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Lindahl, Lise M.; Fredholm, Simon; Joseph, Claudine; Nielsen, Boye Schnack; Jønson, Lars; Willerslev-Olsen, Andreas; Gluud, Maria; Blümel, Edda; Petersen, David L. and Sibbesen, Nina, et al. (2016) In Oncotarget 7(29). p.45730-45744
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... (More)

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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@article{7ab0c4a3-5744-471a-82fd-53abc446081e,
  abstract     = {<p>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.</p>},
  author       = {Lindahl, Lise M. and Fredholm, Simon and Joseph, Claudine and Nielsen, Boye Schnack and Jønson, Lars and Willerslev-Olsen, Andreas and Gluud, Maria and Blümel, Edda and Petersen, David L. and Sibbesen, Nina and Hu, Tengpeng and Nastasi, Claudia and Krejsgaard, Thorbjørn and Jæhger, Ditte and Persson, Jenny L. and Mongan, Nigel and Wasik, Mariusz A. and Litvinov, Ivan V. and Sasseville, Denis and Koralov, Sergei B. and Bonefeld, Charlotte M. and Geisler, Carsten and Woetmann, Anders and Ralfkiaer, Elisabeth and Iversen, Lars and Odum, Niels},
  issn         = {1949-2553},
  keyword      = {Cutaneous T-cell lymphoma (CTCL),IL-2,In situ,miR-21,STAT5},
  language     = {eng},
  month        = {06},
  number       = {29},
  pages        = {45730--45744},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {STAT5 induces miR-21 expression in cutaneous T cell lymphoma},
  url          = {http://dx.doi.org/10.18632/oncotarget.10160},
  volume       = {7},
  year         = {2016},
}