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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.; Sibbesen, Nina; Hu, Tengpeng; Nastasi, Claudia; Krejsgaard, Thorbjørn; Jæhger, 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

Authors

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 P. 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



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., …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 http://eprints.nottingham.ac.uk/id/eprint/36661
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=10160
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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