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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.

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.

Fil: Grabbe, Lester L. University of Hull; Reino Unido Fil: Beentjes, Pancratius C. Tilburg University. Faculty of Catholic Theology; Paises Bajos Fil: Ben-Dov, Jonathan. Haifa University. Department of Bible; Israel Fil: Cook, Steve. Louisville Presbyterian Theological Seminary; Estados Unidos Fil: Frolov, Serge. Southern Methodist University; Estados Unidos Fil: Leuchter, Mark. Temple University ; Estados Unidos Fil: Levin, Christoph. Ludwig-MaximiliansUniversität; Alemania Fil: Middlemas, Jill. University of Zürich. Theology Faculty; Suiza Fil: Petersen, David L. Emory University. Candler School of Theology; Estados Unidos Fil: Sweeney, Marvin A. Claremont Graduate University; Estados Unidos Fil: Tiemeyer, Lena Sofia. University of Aberdeen; Escocia Fil: Wright, Peter Matthews. Colorado College. Department of Religion; Estados Unidos Resumen: Esta colección de ensayos, producto de las reuniones del Grupo Textos Proféticos y sus Contextos Antiguos, de la SBL, examina como se construyó la profecía en literatura bíblica como los profetas anteriores, los profetas posteriores, Crónicas, y Daniel, e incluso en el Corán. Al reconocer que estos textos no describen simplemente los fenómenos proféticos, sino que más bien representan a los profetas de acuerdo a varias categorías convencionales o sus propios puntos de vista individuales, los ensayos analizan la manera en la que la profecía y los profetas son retratados en estos escritos, con el fin de entender mejor como fueron estructurados por sus respectivos autores. Abstract: This collection of essays, arising from the meetings of the SBL’s Prophetic Texts and Their Ancient Contexts Group, examines how prophecy has been constructed in biblical literature such as the Former Prophets, the Latter Prophets, Chronicles, and Daniel, and even in the Qur’an. Recognizing that these texts do not simply describe the prophetic phenomena but rather depict prophets according to various conventional categories or their own individual points of view, the essays analyze the way prophecy or prophets are portrayed in these writings to better understand how they were structured by their respective authors.