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Simple Summary: JAK3 plays an important role in the pathogenesis of cutaneous T cell lymphoma. JAK3 belongs to the Janus kinase family of receptor-associated tyrosine kinases located in cytoplasm adjacent to the plasma membrane. In this study, we show that JAK3 can also be ectopically expressed in the nucleus in CTCL cell lines and primary cells from CTCL patients. Importantly, JAK3 interacts with the nuclear protein RNA polymerase II and phosphorylates Histone H3. Thus, our data provide first evidence for nuclear expression of JAK3 and interactions with key nuclear proteins in malignant T cells suggesting a novel non-canonical role in CTCL. Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro—an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL. [ABSTRACT FROM AUTHOR]

Altered miRNA expressions are assigned pathogenic properties in several cancers including mycosis fungoides and could play a role in the early onset of the disease. The aim of this study was to examine disease-specific miRNA expression in early-stage mycosis fungoides patch and plaque lesions. A quantitative real-time PCR platform of 384 human miRNAs was used to study miRNA expression in 154 diagnostic mycosis fungoides biopsies. A total of 110 miRNAs were significantly differentially expressed (>2-fold, p < 0.05) between plaque lesions and healthy controls, and 90 miRNAs (>2-fold, p < 0.05) differed between patch lesions and healthy controls. Moreover, 13 miRNAs differed in expression between patch and plaque lesions. Early-stage mycosis fungoides exhibited miRNA features that overlapped with those of psoriasis. However, 39 miRNAs, including miR-142-3p, miR-150 and miR-146b, were specific to mycosis fungoides. In conclusion, early-stage mycosis fungoides expresses a distinct miRNA profile, indicating that miRNAs could play a role in the early development of mycosis fungoides. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL. [ABSTRACT FROM AUTHOR]

Altered miRNA expressions are assigned pathogenic properties in several cancers including mycosis fungoides (MF) and could play a role in the early onset of the disease. To examine disease specific miRNA expression in early-stage MF patch and plaque lesions. We used a qRT-PCR platform of 384 human miRNAs to study the miRNA expression in 154 diagnostic MF biopsies. One-hundred-and-ten miRNAs were significantly differentially expressed (>2-fold, P<0.05) between plaque lesions and healthy controls, and 90 miRNAs (>2-fold, P<0.05) differed between patch lesions and healthy controls. Moreover, 13 miRNAs differed in expression between patch and plaque lesions. Early-stage MF exhibited miRNA features overlapping with psoriasis. However, 39 miRNAs, including miR-142-3p, miR-150 and miR-146b, were MF specific. Early-stage MF express a distinct miRNA profile indicating that miRNAs play a role in the early development of MF. [ABSTRACT FROM AUTHOR]

T cell activation is intimately linked to metabolism, as distinct metabolic requirements support the functional and phenotypical differences between quiescent and activated T cells. Metabolic transition from mitochondrial oxidative phosphorylation to aerobic glycolysis is crucial for a proper T cell activation. However, the role of tricarboxylic acid cycle (TCA), and in particular succinate dehydrogenase (SDH) in activated T cells needs further elucidation. Here we show that inhibition of SDH during activation of T cells results in strong impairment of proliferation, expression of activation markers, and production of key inflammatory cytokines, despite a concomitant increase in glycolytic metabolic activity. Similar effect of SDH inhibition were demonstrated in pre-activated T cell. Interestingly, itaconic acid, an endogenous SDH inhibitor released from activated macrophages and dendritic cells, had no immunomodulator effect. Taken together, our findings demonstrate that SDH enzyme fitness is critical for mounting and maintaining appropriate activation and function of human T cells. [ABSTRACT FROM AUTHOR]

and its toxins have been linked to disease progression and mortality in advanced stages of cutaneous T-cell lymphoma (CTCL). CD8+ T cells play a crucial role in anti-cancer responses and high CD8+ T cell numbers in tumor lesions are associated with a favorable prognosis in CTCL. Here, we show that CD8+ T cells from both healthy donors and Sézary syndrome patients are highly susceptible to cell death induced by Staphylococcal alpha-toxin, whereas malignant T cells are not. Importantly, alpha-toxin almost completely blocks cytotoxic killing of CTCL tumor cells by peptide-specific CD8+ T cells, leading to their escape from induced cell death and continued proliferation. These findings suggest that alpha-toxin may favor the persistence of malignant CTCL cells in vivo by inhibiting CD8+ T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with Staphylococcus aureus may contribute to cancer immune evasion and disease progression in CTCL. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]