24 results on '"Willerslev-Olsen, Andreas"'
Search Results
2. Endolysin Inhibits Skin Colonization by Patient-Derived Staphylococcus Aureus and Malignant T-Cell Activation in Cutaneous T-Cell Lymphoma
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Pallesen, Emil M.H., Gluud, Maria, Vadivel, Chella Krishna, Buus, Terkild B., de Rooij, Bob, Zeng, Ziao, Ahmad, Sana, Willerslev-Olsen, Andreas, Röhrig, Christian, Kamstrup, Maria R., Bay, Lene, Lindahl, Lise, Krejsgaard, Thorbjørn, Geisler, Carsten, Bonefeld, Charlotte M., Iversen, Lars, Woetmann, Anders, Koralov, Sergei B., Bjarnsholt, Thomas, Frieling, Johan, Schmelcher, Mathias, and Ødum, Niels
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- 2023
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3. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
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Gluud, Maria, Pallesen, Emil M. H., Buus, Terkild B., Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Kamstrup, Maria R., Bzorek, Michael, Danielsen, Maria, Bech, Rikke, Monteiro, Madalena N., Blümel, Edda, Willerslev-Olsen, Andreas, Lykkebo-Valløe, Anders, Vadivel, Chella Krishna, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menne, Geisler, Carsten, Becker, Jürgen C., Koralov, Sergei B., Iversen, Lars, Litman, Thomas, Woetmann, Anders, and Ødum, Niels
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- 2023
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4. Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma
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Willerslev-Olsen, Andreas, Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Buus, Terkild B., Pallesen, Emil M.H., Gluud, Maria, Bzorek, Michael, Nielsen, Boye S., Kamstrup, Maria R., Rittig, Anne Hald, Bonefeld, Charlotte M., Krejsgaard, Thorbjørn, Geisler, Carsten, Koralov, Sergei B., Litman, Thomas, Becker, Jurgen C., Woetmann, Anders, Iversen, Lars, and Odum, Niels
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- 2021
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5. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma
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Lindahl, Lise M., Willerslev-Olsen, Andreas, Gjerdrum, Lise M.R., Nielsen, Pia R., Blümel, Edda, Rittig, Anne H., Celis, Pamela, Herpers, Bjorn, Becker, Jürgen C., Stausbøl-Grøn, Birgitte, Wasik, Mariusz A., Gluud, Maria, Fredholm, Simon, Buus, Terkild B., Johansen, Claus, Nastasi, Claudia, Peiffer, Lukas, Kubat, Linda, Bzorek, Michael, Eriksen, Jens O., Krejsgaard, Thorbjørn, Bonefeld, Charlotte M., Geisler, Carsten, Mustelin, Tomas, Langhoff, Erik, Givskov, Michael, Woetmann, Anders, Kilian, Mogens, Litman, Thomas, Iversen, Lars, and Odum, Niels
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- 2019
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6. SATB1 in Malignant T Cells
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Fredholm, Simon, Willerslev-Olsen, Andreas, Met, Özcan, Kubat, Linda, Gluud, Maria, Mathiasen, Sarah L., Friese, Christina, Blümel, Edda, Petersen, David L., Hu, Tengpeng, Nastasi, Claudia, Lindahl, Lise M., Buus, Terkild B., Krejsgaard, Thorbjørn, Wasik, Mariusz A., Kopp, Katharina L., Koralov, Sergei B., Persson, Jenny L., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Iversen, Lars, Becker, Jürgen C., and Ødum, Niels
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- 2018
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7. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study
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Lindahl, Lise M., Besenbacher, Søren, Rittig, Anne H., Celis, Pamela, Willerslev-Olsen, Andreas, Gjerdrum, Lise M.R., Krejsgaard, Thorbjørn, Johansen, Claus, Litman, Thomas, Woetmann, Anders, Odum, Niels, and Iversen, Lars
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- 2018
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8. Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome
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Willerslev-Olsen, Andreas, Buus, Terkild B., Nastasi, Claudia, Blümel, Edda, Gluud, Maria, Bonefeld, Charlotte M., Geisler, Carsten, Lindahl, Lise M., Vermeer, Maarten, Wasik, Mariusz A., Iversen, Lars, Becker, Jürgen C., Andersen, Mads Hald, Gjerdrum, Lise M. R., Litvinov, Ivan V., Litman, Thomas, Krejsgaard, Thorbjørn, Woetmann, Anders, and Ødum, Niels
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- 2020
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9. Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma
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Willerslev-Olsen, Andreas, Krejsgaard, Thorbjørn, Lindahl, Lise M., Litvinov, Ivan V., Fredholm, Simon, Petersen, David L., Nastasi, Claudia, Gniadecki, Robert, Mongan, Nigel P., Sasseville, Denis, Wasik, Mariusz A., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Iversen, Lars, Kilian, Mogens, Koralov, Sergei B., and Odum, Niels
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- 2016
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10. Elucidating the role of interleukin-17F in cutaneous T-cell lymphoma
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Krejsgaard, Thorbjørn, Litvinov, Ivan V., Wang, Yang, Xia, Lixin, Willerslev-Olsen, Andreas, Koralov, Sergei B., Kopp, Katharina L., Bonefeld, Charlotte M., Wasik, Mariusz A., Geisler, Carsten, Woetmann, Anders, Zhou, Youwen, Sasseville, Denis, and Odum, Niels
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- 2013
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11. miRNA Signature in Early-stage Mycosis Fungoides.
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SØRENSEN, Sissel T., LITMAN, Thomas, GLUUD, Maria, CELIS, Pamela, TORRES-RUSILLO, Sara, WILLERSLEV-OLSEN, Andreas, ØDUM, Niels, IVERSEN, Lars, and LINDAHL, Lise M.
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MYCOSIS fungoides ,GENE expression ,MICRORNA ,CUTANEOUS T-cell lymphoma - Abstract
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]
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- 2022
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12. The Thioredoxin-Interacting Protein TXNIP Is a Putative Tumour Suppressor in Cutaneous T-Cell Lymphoma.
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Stolearenco, Veronica, Levring, Trine B., Nielsen, Helene Myrtue, Lindahl, Lise, Fredholm, Simon, Kongsbak-Wismann, Martin, Willerslev-Olsen, Andreas, Buus, Terkild B., Nastasi, Claudia, Hu, Tengpeng, Gluud, Maria, Côme, Christophe R.M., Krejsgaard, Thorbjørn, Iversen, Lars, Bonefeld, Charlotte Menné, Grønbæk, Kirsten, Met, Özcan, Woetmann, Anders, Ødum, Niels, and Geisler, Carsten
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CUTANEOUS T-cell lymphoma ,THIOREDOXIN-interacting protein ,CANCER cells ,T cells ,CELL lines ,O6-Methylguanine-DNA Methyltransferase ,ANAPLASTIC lymphoma kinase - Abstract
Background: The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients. Objectives: To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL). Methods: CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 – an inhibitor of enhancer of zeste homolog 2 (EZH2) methyltransferase activity or assessed by bisulphite sequencing for TXNIP promoter methylation. Methylation was also assessed with the demethylating agent 5-azacytidine (5AZA). Finally, TXNIP was overexpressed in the malignant PB2B cell line via plasmid transduction, and the effect of TXNIP was further analysed by flow cytometry. Results: We report on low expression of TXNIP protein in all cell lines representing different subtypes and stages of CTCL when compared to non-malignant T cells. Epigenetic silencing and other mechanisms were involved in the repression of TXNIP whereas forced expression of TXNIP strongly inhibited proliferation of malignant T cells. Conclusions: Epigenetic silencing and other as yet unknown mechanisms repress TXNIP expression in malignant T cells. As forced expression of TXNIP inhibits malignant proliferation, we propose that TXNIP is a putative tumour suppressor in CTCL. [ABSTRACT FROM AUTHOR]
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- 2021
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13. MicroRNA-93 Targets p21 and Promotes Proliferation in Mycosis Fungoides T Cells.
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Gluud, Maria, Fredholm, Simon, Blümel, Edda, Willerslev-Olsen, Andreas, Buus, Terkild Brink, Nastasi, Claudia, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menné, Woetmann, Anders, Iversen, Lars, Litman, Thomas, Geisler, Carsten, Ødum, Niels, and Lindahl, Lise M.
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MYCOSIS fungoides ,T cells ,CYCLIN-dependent kinases ,CANCER cells ,CUTANEOUS T-cell lymphoma ,CYCLIN-dependent kinase inhibitors ,CELL cycle - Abstract
Background: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a lymphoproliferative disorder characterized by proliferation of malignant T cells in a chronic inflammatory environment in the skin. The nature of MF is still not fully understood, but aberrant microRNA (miR) expression and function seem to play an important role in the pathogenesis and disease progression and have been proposed as a putative disease marker. Recent studies have reported aberrant expression of miR-93 in situin MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown. Objective: Here, we provide the first evidence that miR-93 targets the cell cycle regulator cyclin-dependent kinase inhibitor p21 and promotes growth of malignant T cells in MF. Methods/Results: Thus, inhibition of miR-93 in MF patient-derived malignant T-cell lines increases expression of p21 and inhibition of malignant proliferation. Notably, treatment with the histone deacetylase inhibitor Vorinostat (SAHA) reduces miR-93 expression and enhances p21 expression in the malignant T cells. Importantly, transfection with an miR-93 mimic partly blocks SAHA-induced p21 expression. Conclusions: we provide evidence that enhanced expression of the putative oncogenic miR, miR-93, represses the cell cycle inhibitor p21 and promotes proliferation of malignant T cells. Moreover, we demonstrate that SAHA triggers p21 expression – at least partly – through an inhibition of miR-93. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Expression of the Voltage-Gated Potassium Channel Kv1.3 in Lesional Skin from Patients with Cutaneous T-Cell Lymphoma and Benign Dermatitis.
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Hu, Tengpeng, Krejsgaard, Thorbjørn, Nastasi, Claudia, Buus, Terkild Brink, Nansen, Anneline, Hald, Andreas, Spee, Pieter, Nielsen, Pia Rude, Blümel, Edda, Gluud, Maria, Willerslev-Olsen, Andreas, Woetmann, Anders, Bzorek, Michael, Eriksen, Jens O., Ødum, Niels, Rahbek Gjerdrum, Lise Mette, Buus, Terkild Brink, Nielsen, Pia Rude, Eriksen, Jens O, and Rahbek Gjerdrum, Lise Mette
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CUTANEOUS T-cell lymphoma ,POTASSIUM channels ,MYCOSIS fungoides ,SKIN inflammation ,SEZARY syndrome ,T cells ,BIOPSY ,SKIN ,IMMUNOHISTOCHEMISTRY ,ARTHRITIS Impact Measurement Scales ,SKIN tumors ,MEMBRANE proteins ,CELL lines ,CHEMICAL inhibitors - Abstract
Background: The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed by effector memory T cells (TEM) and plays an important role in their activation and proliferation. Mycosis fungoides (MF), the most common subtype of cutaneous T-cell lymphoma (CTCL), was recently proposed to be a malignancy of skin-resident TEM. However, the expression of Kv1.3 in CTCL has not been investigated.Objectives: This study aims to examine the expression of Kv1.3 in situ and in vitro in CTCL.Methods: The expression of Kv1.3 was examined by immunohistochemistry in skin lesions from 38 patients with MF, 4 patients with Sézary syndrome (SS), and 27 patients with benign dermatosis. In 4 malignant T-cell lines of CTCL (Myla2059, PB2B, SeAx, and Mac2a) and a non-malignant T-cell line (MyLa1850), the expression of Kv1.3 was determined by flow cytometry. The proliferation of those cell lines treated with various concentrations of Kv1.3 inhibitor ShK was measured by 3H-thymdine incorporation.Results: Half of the MF patients (19/38) displayed partial Kv1.3 expression including 1 patient with moderate Kv1.3 positivity, while the other half (19/38) exhibited Kv1.3 negativity. An almost identical distribution was observed in patients with benign conditions, that is, 44.4% (12/27) were partially positive for Kv1.3 including 1 patient with moderate Kv1.3 positivity, while 55.6% (15/27) were Kv1.3 negative. In contrast, 3 in 4 SS patients displayed partial Kv1.3 positivity including 2 patients with weak staining and 1 with moderate staining, while 1 in 4 SS patients was Kv1.3 negative. In addition, all malignant T-cell lines, and a non-malignant T-cell line, displayed low Kv1.3 surface expression with a similar pattern. Whereas 2 cell lines (PB2B and Mac2a) were sensitive to Kv1.3 blockade, the other 2 (Myla2059 and SeAx) were completely resistant.Conclusions: We provide the first evidence of a heterogeneous Kv1.3 expression in situ in CTCL lesions. [ABSTRACT FROM AUTHOR]- Published
- 2020
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15. Staphylococcus aureus alpha-toxin inhibits CD8+ T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma.
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Blümel, Edda, Munir Ahmad, Shamaila, Nastasi, Claudia, Willerslev-Olsen, Andreas, Gluud, Maria, Fredholm, Simon, Hu, Tengpeng, Surewaard, Bas G. J., Lindahl, Lise M., Fogh, Hanne, Koralov, Sergei B., Rahbek Gjerdrum, Lise Mette, Clark, Rachael A., Iversen, Lars, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menné, Geisler, Carsten, Becker, Jürgen C., Woetmann, Anders, and Andersen, Mads Hald
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CUTANEOUS T-cell lymphoma ,CANCER cells ,STAPHYLOCOCCUS aureus ,T cells ,CELL death ,SEZARY syndrome ,CYANOBACTERIAL toxins - Abstract
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]- Published
- 2020
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16. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma.
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Blümel, Edda, Willerslev-Olsen, Andreas, Gluud, Maria, Lindahl, Lise M., Fredholm, Simon, Nastasi, Claudia, Krejsgaard, Thorbjørn, Surewaard, Bas G. J., Koralov, Sergei B., Hu, Tengpeng, Persson, Jenny L., Bonefeld, Charlotte Menné, Geisler, Carsten, Iversen, Lars, Becker, Jürgen C., Andersen, Mads Hald, Woetmann, Anders, Buus, Terkild Brink, and Ødum, Niels
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T cells , *CUTANEOUS T-cell lymphoma , *SEZARY syndrome , *CELL death , *STAPHYLOCOCCUS aureus - Abstract
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]
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- 2019
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17. A novel BLK-induced tumor model.
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Petersen, David Leander, Berthelsen, Jens, Willerslev-Olsen, Andreas, Fredholm, Simon, Dabelsteen, Sally, Bonefeld, Charlotte Menné, Geisler, Carsten, and Woetmann, Anders
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PROTEIN-tyrosine kinases ,PROTEIN kinases ,B cell receptors ,CELL receptors ,ONCOGENES - Abstract
B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK--induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK--driven lymphomagenesis and screening of novel BLK inhibitors in vivo. [ABSTRACT FROM AUTHOR]
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- 2017
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18. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation.
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Krejsgaard, Thorbjørn, Willerslev-Olsen, Andreas, Lindahl, Lise M., Bonefeld, Charlotte M., Koralov, Sergei B., Geisler, Carsten, Wasik, Mariusz A., Gniadecki, Robert, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, and Odum, Niels
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STAPHYLOCOCCAL diseases , *ENTEROTOXINS , *LYMPHOMAS , *IMMUNODEFICIENCY , *ANTIBIOTICS - Abstract
Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. Here, we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3-mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease. [ABSTRACT FROM AUTHOR]
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- 2014
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19. IL-15 and IL-17F are differentially regulated and expressed in mycosis fungoides (MF).
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Willerslev-Olsen, Andreas, Litvinov, Ivan V., Fredholm, Simon M., Petersen, David L., Sibbesen, Nina A., Gniadecki, Robert, Qian Zhang, Bonefeld, Charlotte M., Wasik, Mariusz A., Geisler, Carsten, Zhou, Youwen, Woetmann, Anders, Sasseville, Denis, Krejsgaard, Thorbjørn, and Ødum, Niels
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- 2014
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20. Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma.
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Willerslev-Olsen, Andreas, Krejsgaard, Thorbjørn, Lindahl, Lise M., Bonefeld, Charlotte Menne, Wasik, Mariusz A., Koralov, Sergei B., Geisler, Carsten, Kilian, Mogens, Iversen, Lars, Woetmann, Anders, and Odum, Niels
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T-cell lymphoma , *BACTERIAL diseases , *STAPHYLOCOCCUS aureus , *ENTEROTOXINS , *SUPERANTIGENS , *IMMUNODEFICIENCY - Abstract
In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells. [ABSTRACT FROM AUTHOR]
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- 2013
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21. Vascular endothelial growth factor receptor-3 expression in mycosis fungoides.
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Pedersen, Ida Holst, Willerslev-Olsen, Andreas, Vetter-Kauczok, Claudia, Krejsgaard, Thorbjørn, Lauenborg, Britt, Kopp, Katharina Luise, Geisler, Carsten, Bonefeld, Charlotte M., Zhang, Qian, Wasik, Mariusz A., Dabelsteen, Sally, Woetmann, Anders, Becker, Jurgen C., and Odum, Niels
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VASCULAR endothelial growth factor receptors , *MYCOSIS fungoides , *LYMPHOMAS , *TUMORS , *STROMAL cells , *T cells - Abstract
Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal cells irrespective of the disease stage. The natural VEGFR-3 ligand, VEGF-C, partially protected malignant T-cell lines from growth inhibition by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA). Whereas the malignant T cells did not produce VEGF-C in vitro, its expression was induced during tumor formation in vivo in a xenograft mouse model of MF. In conclusion, malignant and stromal cells express high levels of VEGFR-3 in all stages of MF. Moreover, malignant T cells trigger enhanced VEGF-C expression in fibroblasts, suggesting that cross-talk between tumor and stromal cells plays a role in lymphangiogenesis and possibly disease progression. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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22. JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL).
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Vadivel, Chella Krishna, Gluud, Maria, Torres-Rusillo, Sara, Boding, Lasse, Willerslev-Olsen, Andreas, Buus, Terkild B., Nielsen, Tea Kirkegaard, Persson, Jenny L., Bonefeld, Charlotte M., Geisler, Carsten, Krejsgaard, Thorbjorn, Fuglsang, Anja T., Odum, Niels, and Woetmann, Anders
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CELL nuclei ,GENE expression ,PHOSPHORYLATION ,SKIN diseases ,T cells ,TRANSFERASES ,NUCLEAR proteins ,SEZARY syndrome ,T-cell lymphoma ,SIGNAL peptides ,IN vitro studies ,JANUS kinases - Abstract
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]
- Published
- 2021
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23. MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas.
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Gluud, Maria, Willerslev-Olsen, Andreas, Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Buus, Terkild B., Andersen, Mads Hald, Bonefeld, Charlotte Menne, Krejsgaard, Thorbjorn, Litvinov, Ivan V., Iversen, Lars, Becker, Jürgen C., Persson, Jenny L., Koralov, Sergei B., Litman, Thomas, Geisler, Carsten, Woetmann, Anders, and Odum, Niels
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SKIN disease diagnosis , *SKIN disease treatment , *MYCOSIS fungoides , *SKIN diseases , *T-cell lymphoma , *MICRORNA - Abstract
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]
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- 2020
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24. Bio-O1-07 - miRNA signature in early-stage mycosis fungoides.
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Sørensen, Sissel T, Litman, Thomas, Gluud, Maria, Celis, Pamela, Torres-Rusillo, Sara, Willerslev-Olsen, Andreas, Odum, Niels, Iversen, Lars, and Lindahl, Lise M
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MYCOSIS fungoides , *MICRORNA , *CONFERENCES & conventions - Abstract
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]
- Published
- 2021
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