TY - JOUR

T1 - STAT5 induces miR-21 expression in cutaneous T cell lymphoma

AU - Lindahl, Lise M.

AU - Fredholm, Simon

AU - Joseph, Claudine Vanessa

AU - Nielsen, Boye Schnack

AU - Jønson, Lars

AU - Willerslev-Olsen, Andreas

AU - Gluud, Maria

AU - Blümel, Edda

AU - Petersen, David L.

AU - Sibbesen, Nina

AU - Hu, Tengpeng

AU - Nastasi, Claudia

AU - Krejsgaard, Thorbjørn

AU - Jæhger, Ditte

AU - Persson, Jenny L.

AU - Mongan, Nigel

AU - Wasik, Mariusz A.

AU - Litvinov, Ivan V.

AU - Sasseville, Denis

AU - Koralov, Sergei B.

AU - Bonefeld, Charlotte M.

AU - Geisler, Carsten

AU - Andersen, Anders Woetmann

AU - Ralfkiaer, Elisabeth

AU - Iversen, Lars

AU - Odum, Niels

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Cutaneous T-cell lymphoma (CTCL)

KW - IL-2

KW - In situ

KW - miR-21

KW - STAT5

U2 - 10.18632/oncotarget.10160

DO - 10.18632/oncotarget.10160

M3 - Journal article

C2 - 27329723

AN - SCOPUS:84979929947

VL - 7

SP - 45730

EP - 45744

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 29

ER -