STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Lindahl, Lise M.; Fredholm, Simon; Joseph, Claudine; Nielsen, Boye Schnack; J�nson, Lars; Willerslev-Olsen, Andreas; Gluud, Maria; Bl�mel, Edda; Petersen, David L.; Sibbesen, Nina; Hu, Tengpeng; Nastasi, Claudia; Krejsgaard, Thorbj�rn; J�hger, Ditte; Persson, Jenny L.; Mongan, Nigel P.; Wasik, Mariusz A.; Litvinov, Ivan V.; Sasseville, Denis; Koralov, Sergei B.; Bonefeld, Charlotte M.; Geisler, Carsten; Woetmann, Anders; Ralfkiaer, Elisabeth; Iversen, Lars; Odum, Niels

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 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.

Citation

Lindahl, L. M., Fredholm, S., Joseph, C., Nielsen, B. S., Jønson, L., Willerslev-Olsen, A., Gluud, M., Blümel, E., Petersen, D. L., Sibbesen, N., Hu, T., Nastasi, C., Krejsgaard, T., Jæhger, D., Persson, J. L., Mongan, N. P., Wasik, M. A., Litvinov, I. V., Sasseville, D., Koralov, S. B., …Odum, N. (2016). STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Oncotarget, https://doi.org/10.18632/oncotarget.10160

• Journal Article Type: Article
• Acceptance Date: Jun 3, 2016
• Publication Date: Jun 18, 2016
• Deposit Date: Sep 15, 2016
• Publicly Available Date: Sep 15, 2016
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.18632/oncotarget.10160
• Keywords: MiR-21, in situ, STAT5, IL-2, Cutaneous T-cell lymphoma (CTCL)
• Public URL: https://nottingham-repository.worktribe.com/output/794414
• Publisher URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=10160
• Contract Date: Sep 15, 2016