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.
Highlights
Primary cutaneous T cell lymphomas (CTCL) represent a heterogeneous group of lymphoproliferative disorders characterized by proliferation of skin-homing malignant T cells in a chronic inflammatory environment [1]
Microbes have been implicated in disease progression in CTCL [22,23,24], and staphylococcal enterotoxins were recently shown to trigger aberrant JAK3/STAT3 signaling in malignant T cells [25] suggesting a direct link between bacterial infection/ colonization and activation of this oncogenic pathway in malignant T cells
We provide the evidence that miR-21 expression is induced by the IL-2Rg-binding cytokines IL-2 and IL-15, and is up-regulated directly by STAT5 in malignant T cells
Summary
Primary cutaneous T cell lymphomas (CTCL) represent a heterogeneous group of lymphoproliferative disorders characterized by proliferation of skin-homing malignant T cells in a chronic inflammatory environment [1]. In the early stages of CTCL the IL-2Rgc-signaling cytokines IL-2, IL-4, IL- 7, IL-15, and IL-21 activate STAT3 and/or STAT5, promoting malignant cell proliferation and survival [6,7,8,9] In advanced progressive CTCL, JAK3 and STAT3/STAT5 are constitutively activated in a cytokine independent manner [10, 12] In addition to the well-established role in proliferation and anti-apoptosis, the JAK3/STAT pathway drives expression of regulatory and pro-inflammatory cytokines such as IL-5, IL-9, IL-10, IL-13, IL-17, IL-22, and lymphotoxin alpha, chemokines, and factors promoting angiogenesis [13,14,15,16,17,18,19,20,21]. Microbes have been implicated in disease progression in CTCL [22,23,24], and staphylococcal enterotoxins were recently shown to trigger aberrant JAK3/STAT3 signaling in malignant T cells [25] suggesting a direct link between bacterial infection/ colonization and activation of this oncogenic pathway in malignant T cells
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