Search

Summary: Cutaneous T-cell lymphoma (CTCL) comprises distinct and often progressive stages of skin involvement by patches, plaques, and tumors. We have previously demonstrated that CTCL-derived malignant T-cell lines display loss of a tumor suppressor SHP-1 tyrosine phosphatase because of epigenetic silencing of its gene. The silencing is induced by an activated phosphorylated (p)-STAT3 transcription factor in cooperation with DNA methyltransferase 1 (DNMT1), the key member of the epigenetic gene silencing machinery. To determine at which stage of CTCL the loss of SHP-1 occurs and how it correlates with the expression of (p)-STAT3 and DNMT1, we examined by immunohistochemistry 47 formalin-fixed skin biopsies from various stages of CTCL. Six pairs of the biopsies were obtained before and after CTCL progression at the patch or plaque and tumor stage, respectively. In 5 of these pairs, we identified loss of SHP-1 expression in atypical lymphocytes at the tumor stage; less prominent SHP-1 loss was noted in 3 biopsies from the earlier stage. The SHP-1 loss was also observed in 5 of 6 tumor, 12 of 18 plaque, and only 2 of 11 patch stages in patients with single biopsies. The expression of (p)-STAT3 and DNMT1 could be identified in almost all cases in at least a subset of the lesional cells. Based on these findings, we postulate that expression of (p)-STAT3 and DNMT1 occurs at the early stages of CTCL, and that this expression alone seems insufficient to induce loss of SHP-1 expression. In turn, SHP-1 loss correlates with, and may contribute to, progression of CTCL. [Copyright &y& Elsevier]

A response by Thorbjørn Krejsgaard and colleagues to a letter to the editor on their article "Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway" in the 2011 issue is presented.

IL-17 is a proinflammatory cytokine that is crucial for the host's protection against a range of extracellular pathogens. However, inappropriately regulated expression of IL-17 is associated with the development of inflammatory diseases and cancer. In cutaneous T-cell lymphoma (CTCL), malignant T cells gradually accumulate in skin lesions characterized by massive chronic inflammation, suggesting that IL-17 could be involved in the pathogenesis. In this study we show that IL-17 protein is present in 10 of 13 examined skin lesions but not in sera from 28 CTCL patients. Importantly, IL-17 expression is primarily observed in atypical lymphocytes with characteristic neoplastic cell morphology. In accordance, malignant T-cell lines from CTCL patients produce IL-17 and the synthesis is selectively increased by IL-2 receptor β chain cytokines. Small-molecule inhibitors or small interfering RNA against Jak3 and signal transducer and activator of transcription 3 (Stat3) reduce the production of IL-17, showing that the Jak3/Stat3 pathway promotes the expression of the cytokine. In summary, our findings indicate that the malignant T cells in CTCL lesions express IL-17 and that this expression is promoted by the Jak3/Stat3 pathway. [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]

Abstract: Early T lymphocyte activator 1 (Eta-1), also known as Osteopontin, is a cytokine produced by macrophages and T lymphocytes. It is involved in the regulation of IL-12 and IL-10 expression in macrophages and stimulates the polarization of T cells to the Th1 subset. Three promoter polymorphisms of the human Eta-1 gene, −443T/C, −156delG/G, −66T/G, were investigated for possible influence on gene expression. Electrophoretic mobility shift assays (EMSA) with nuclear extract from the human myeloid leukaemia premonocyte cell line, THP-1, revealed sequence specific binding of the transcription factor Sp1 to the −66T allele but not the −66G allele, and haplotype −443C/−156G/−66T showed a marked increase in promoter activity of a luciferase reporter gene. Thus, a substitution of the T-base with G at position −66 in the Eta-1 promoter modulates the promoter activity of the Eta-1 gene, which might influence the Th1 versus Th2 balance. These observations are discussed in relation to a recently reported related observation on the same gene, and it is argued that discrepancies between reporter gene assays in the two studies may be due to the use of different cell lines and may reflect requirements for different transcription factors in cells involved in immune responses compared with other cells. [Copyright &y& Elsevier]

Studies the functional role of STAT6 serine phosphorylation and the kinases and phosphatases involved. Impact of the inhibition of protein phosphatase 2A on the serine phosphorylation of STAT6 and the inhibition of the DNA binding of STAT6; Analysis of pertinent topics and relevant issues; Implications on studies of enzyme catalysis and regulation.