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 Odum, Anders Woetmann

    Publikation: Bidrag til tidsskriftArtikelForskningpeer review

    Abstrakt

    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.

    OriginalsprogEngelsk
    Sider (fra-til)1939-1947
    Antal sider9
    TidsskriftCell Cycle
    Vol/bind12
    Udgave nummer12
    DOI
    StatusUdgivet - 15 jun. 2013

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