STAT5 induces miR-21 expression in cutaneous T cell lymphoma
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 sit...
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2016
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| author | 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 |
| author_facet | 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 |
| author_sort | Lindahl, Lise M. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:30:17Z |
| format | Article |
| id | nottingham-36661 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:30:17Z |
| publishDate | 2016 |
| publisher | Impact |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-366612020-05-04T17:55:58Z https://eprints.nottingham.ac.uk/36661/ 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 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. Impact 2016-06-18 Article PeerReviewed 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 and Odum, Niels (2016) STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Oncotarget . ISSN 1949-2553 MiR-21 in situ STAT5 IL-2 Cutaneous T-cell lymphoma (CTCL) http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=10160 doi:10.18632/oncotarget.10160 doi:10.18632/oncotarget.10160 |
| spellingShingle | MiR-21 in situ STAT5 IL-2 Cutaneous T-cell lymphoma (CTCL) 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 STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title | STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title_full | STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title_fullStr | STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title_full_unstemmed | STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title_short | STAT5 induces miR-21 expression in cutaneous T cell lymphoma |
| title_sort | stat5 induces mir-21 expression in cutaneous t cell lymphoma |
| topic | MiR-21 in situ STAT5 IL-2 Cutaneous T-cell lymphoma (CTCL) |
| url | https://eprints.nottingham.ac.uk/36661/ https://eprints.nottingham.ac.uk/36661/ https://eprints.nottingham.ac.uk/36661/ |