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.
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kopp
authors.forename: Ulrik
authors.initials: U
authors.lastname: Ralfkiaer
authors.forename: Lise Mette R
authors.initials: LM
authors.lastname: Gjerdrum
authors.forename: Rikke
authors.initials: R
authors.lastname: Helvad
authors.forename: Ida H
authors.initials: IH
authors.lastname: Pedersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Litman
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hagedorn
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Krejsgaard
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.forename: Lone
authors.initials: L
authors.lastname: Skov
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiaer
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor
keywords: BIC; CTCL; JAK; MF; STAT5; miR-155; miRNA