STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

Katharina L Kopp; Ulrik Ralfkiaer; Lise Mette R Gjerdrum; Rikke Helvad; Ida H Pedersen; Thomas Litman; Lars Jønson; Peter H Hagedorn; Thorbjørn Krejsgaard; Robert Gniadecki; Charlotte M Bonefeld; Lone Skov; Carsten Geisler; Mariusz A Wasik; Elisabeth Ralfkiaer; Niels Ødum; Anders Woetmann

doi:10.4161/cc.24987

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

Katharina L Kopp, Ulrik Ralfkiaer, Lise Mette R Gjerdrum, Rikke Helvad, Ida H Pedersen, Thomas Litman, Lars Jønson, Peter H Hagedorn, Thorbjørn Krejsgaard, Robert Gniadecki, Charlotte M Bonefeld, Lone Skov, Carsten Geisler, Mariusz A Wasik, Elisabeth Ralfkiaer, Niels Ødum, Anders Woetmann

93 Citations (Scopus)

Abstract

The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.

Original language	English
Journal	Cell Cycle
Volume	12
Issue number	12
Pages (from-to)	1939-47
Number of pages	9
ISSN	1538-4101
DOIs	https://doi.org/10.4161/cc.24987
Publication status	Published - 15 Jun 2013

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Kopp, K. L., Ralfkiaer, U., Gjerdrum, L. M. R., Helvad, R., Pedersen, I. H., Litman, T., Jønson, L., Hagedorn, P. H., Krejsgaard, T., Gniadecki, R., Bonefeld, C. M., Skov, L., Geisler, C., Wasik, M. A., Ralfkiaer, E., Ødum, N., & Woetmann, A. (2013). STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle, 12(12), 1939-47. https://doi.org/10.4161/cc.24987

Kopp, KL, Ralfkiaer, U, Gjerdrum, LMR, Helvad, R, Pedersen, IH, Litman, T, Jønson, L, Hagedorn, PH, Krejsgaard, T, Gniadecki, R, Bonefeld, CM, Skov, L , Geisler, C, Wasik, MA, Ralfkiaer, E, Ødum, N & Woetmann, A 2013, 'STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma', Cell Cycle, vol. 12, no. 12, pp. 1939-47. https://doi.org/10.4161/cc.24987

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title = "STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma",

abstract = "The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.",

author = "Kopp, {Katharina L} and Ulrik Ralfkiaer and Gjerdrum, {Lise Mette R} and Rikke Helvad and Pedersen, {Ida H} and Thomas Litman and Lars J{\o}nson and Hagedorn, {Peter H} and Thorbj{\o}rn Krejsgaard and Robert Gniadecki and Bonefeld, {Charlotte M} and Lone Skov and Carsten Geisler and Wasik, {Mariusz A} and Elisabeth Ralfkiaer and Niels {\O}dum and Anders Woetmann",

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doi = "10.4161/cc.24987",

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T1 - STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

AU - Kopp, Katharina L

AU - Ralfkiaer, Ulrik

AU - Gjerdrum, Lise Mette R

AU - Helvad, Rikke

AU - Pedersen, Ida H

AU - Litman, Thomas

AU - Jønson, Lars

AU - Hagedorn, Peter H

AU - Krejsgaard, Thorbjørn

AU - Gniadecki, Robert

AU - Bonefeld, Charlotte M

AU - Skov, Lone

AU - Geisler, Carsten

AU - Wasik, Mariusz A

AU - Ralfkiaer, Elisabeth

AU - Ødum, Niels

AU - Woetmann, Anders

PY - 2013/6/15

Y1 - 2013/6/15

N2 - The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.

AB - The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.

U2 - 10.4161/cc.24987

DO - 10.4161/cc.24987

M3 - Journal article

C2 - 23676217

SN - 1538-4101

VL - 12

SP - 1939

EP - 1947

JO - Cell Cycle

JF - Cell Cycle

IS - 12

ER -

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

Abstract

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