STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Lise M. Lindahl; Simon Fredholm; Claudine Vanessa 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 Mongan; Mariusz A. Wasik; Ivan V. Litvinov; Denis Sasseville; Sergei B. Koralov; Charlotte M. Bonefeld; Carsten Geisler; Anders Woetmann Andersen; Elisabeth Ralfkiaer; Lars Iversen; Niels Odum

doi:10.18632/oncotarget.10160

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Lise M. Lindahl, Simon Fredholm, Claudine Vanessa 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 Mongan, Mariusz A. Wasik, Ivan V. Litvinov, Denis Sasseville, Sergei B. KoralovCharlotte M. Bonefeld, Carsten Geisler, Anders Woetmann Andersen, Elisabeth Ralfkiaer, Lars Iversen^*, Niels Odum

^*Corresponding author af dette arbejde

29 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	OncoTarget
Vol/bind	7
Udgave nummer	29
Sider (fra-til)	45730-45744
Antal sider	15
ISSN	1949-2553
DOI	https://doi.org/10.18632/oncotarget.10160
Status	Udgivet - 2016

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10.18632/oncotarget.10160Licens: CC BY

STAT5 induces miR-21 expression in cutaneous T cell lymphomaForlagets udgivne version, 8,34 MBLicens: CC BY

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Lindahl, L. M., Fredholm, S., Joseph, C. V., 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., Wasik, M. A., Litvinov, I. V., Sasseville, D., ... Odum, N. (2016). STAT5 induces miR-21 expression in cutaneous T cell lymphoma. OncoTarget, 7(29), 45730-45744. https://doi.org/10.18632/oncotarget.10160

Lindahl, LM, Fredholm, S, Joseph, CV, Nielsen, BS, Jønson, L, Willerslev-Olsen, A, Gluud, M, Blümel, E, Petersen, DL, Sibbesen, N, Hu, T, Nastasi, C, Krejsgaard, T, Jæhger, D, Persson, JL, Mongan, N, Wasik, MA, Litvinov, IV, Sasseville, D, Koralov, SB, Bonefeld, CM, Geisler, C , Andersen, AW, Ralfkiaer, E, Iversen, L & Odum, N 2016, 'STAT5 induces miR-21 expression in cutaneous T cell lymphoma', OncoTarget, bind 7, nr. 29, s. 45730-45744. https://doi.org/10.18632/oncotarget.10160

@article{65bf5e12eca54e338e76a5e93e5889d6,

title = "STAT5 induces miR-21 expression in cutaneous T cell lymphoma",

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.",

keywords = "Cutaneous T-cell lymphoma (CTCL), IL-2, In situ, miR-21, STAT5",

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

year = "2016",

doi = "10.18632/oncotarget.10160",

language = "English",

volume = "7",

pages = "45730--45744",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

number = "29",

}

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

SN - 1949-2553

VL - 7

SP - 45730

EP - 45744

JO - Oncotarget

JF - Oncotarget

IS - 29

ER -

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Abstract

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