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 -