43 results on '"Gluud, Maria"'
Search Results
2. Keratinocytes Present Staphylococcus aureus Enterotoxins and Promote Malignant and Nonmalignant T Cell Proliferation in Cutaneous T-Cell Lymphoma
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Zeng, Ziao, Vadivel, Chella Krishna, Gluud, Maria, Namini, Martin R.J., Yan, Lang, Ahmad, Sana, Hansen, Morten Bagge, Coquet, Jonathan, Mustelin, Tomas, Koralov, Sergei B., Bonefeld, Charlotte Menne, Woetmann, Anders, Geisler, Carsten, Guenova, Emmanuella, Kamstrup, Maria R., Litman, Thomas, Gjerdrum, Lise-Mette R., Buus, Terkild B., and Ødum, Niels
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- 2024
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3. 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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4. 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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5. 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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6. Publisher Correction: Inhibition of succinate dehydrogenase activity impairs human T cell activation and function
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Nastasi, Claudia, Willerlev-Olsen, Andreas, Dalhoff, Kristoffer, Ford, Shayne L., Gadsbøll, Anne-Sofie Østergaard, Buus, Terkild Brink, Gluud, Maria, Danielsen, Morten, Litman, Thomas, Bonefeld, Charlotte Mennè, Geisler, Carsten, Ødum, Niels, and Woetmann, Anders
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- 2021
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7. Inhibition of succinate dehydrogenase activity impairs human T cell activation and function
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Nastasi, Claudia, Willerlev-Olsen, Andreas, Dalhoff, Kristoffer, Ford, Shayne L., Gadsbøll, Anne-Sofie Østergaard, Buus, Terkild Brink, Gluud, Maria, Danielsen, Morten, Litman, Thomas, Bonefeld, Charlotte Mennè, Geisler, Carsten, Ødum, Niels, and Woetmann, Anders
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- 2021
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8. 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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9. 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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10. 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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11. miRNA Signature in Early-stage Mycosis Fungoides
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Sørensen, Sissel T., primary, Litman, Thomas, additional, Gluud, Maria, additional, Celis, Pamela, additional, Torres-Rusillo, Sara, additional, Willerslev-Olsen, Andreas, additional, Ødum, Niels, additional, Iversen, Lars, additional, and Lindahl, Lise M., additional
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- 2022
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12. miRNA signature in early-stage mycosis fungoides
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Sørensen, Sissel T, primary, Litman, Thomas, additional, Gluud, Maria, additional, Celis, Pamela, additional, Torres-Rusillo, Sara, additional, Willerslev-Olsen, Andreas, additional, Odum, Niels, additional, Iversen, Lars, additional, and Lindahl, Lise M, additional
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- 2021
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13. Inhibition of succinate dehydrogenase activity impairs human T cell activation and function:[Publisher correction]
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Nastasi, Claudia, Willerlev-Olsen, Andreas, Dalhoff, Kristoffer, Ford, Shayne L., Gadsbøll, Anne Sofie Østergaard, Buus, Terkild Brink, Gluud, Maria, Danielsen, Morten, Litman, Thomas, Bonefeld, Charlotte Mennè, Geisler, Carsten, Ødum, Niels, and Woetmann, Anders
- Subjects
macromolecular substances - Abstract
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.
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- 2021
14. Low SATB1 Expression Promotes IL-5 and IL-9 Expression in Sézary Syndrome
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Herrera, Alberto, Fredholm, Simon, Cheng, Anthony, Mimitou, Eleni P., Seffens, Angelina, Bar-Natan, Michal, Sun, Amy, Latkowski, Jo-Ann, Willerslew-Olsen, Andreas, Buus, Terkild B., Gluud, Maria, Krejsgaard, Thorbjørn, Torres-Rusillo, Sara, Bonefeld, Charlotte Menné, Woetmann, Anders, Geisler, Carsten, Geskin, Larisa J., Ouyang, Zhengqing, Smibert, Peter, Ødum, Niels, and Koralov, Sergei B.
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- 2020
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15. JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)
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Vadivel, Chella Krishna, primary, Gluud, Maria, additional, Torres-Rusillo, Sara, additional, Boding, Lasse, additional, Willerslev-Olsen, Andreas, additional, Buus, Terkild B., additional, Nielsen, Tea Kirkegaard, additional, Persson, Jenny L., additional, Bonefeld, Charlotte M., additional, Geisler, Carsten, additional, Krejsgaard, Thorbjorn, additional, Fuglsang, Anja T., additional, Odum, Niels, additional, and Woetmann, Anders, additional
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- 2021
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16. Cellular Interactions and Inflammation in the Pathogenesis of Cutaneous T-Cell Lymphoma
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Stolearenco, Veronica, primary, Namini, Martin R. J., additional, Hasselager, Siri S., additional, Gluud, Maria, additional, Buus, Terkild B., additional, Willerslev-Olsen, Andreas, additional, Ødum, Niels, additional, and Krejsgaard, Thorbjørn, additional
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- 2020
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17. The Thioredoxin-Interacting Protein TXNIP Is a Putative Tumour Suppressor in Cutaneous T-Cell Lymphoma
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Stolearenco, Veronica, primary, Levring, Trine B., additional, Nielsen, Helene Myrtue, additional, Lindahl, Lise, additional, Fredholm, Simon, additional, Kongsbak-Wismann, Martin, additional, Willerslev-Olsen, Andreas, additional, Buus, Terkild B., additional, Nastasi, Claudia, additional, Hu, Tengpeng, additional, Gluud, Maria, additional, Côme, Christophe R.M., additional, Krejsgaard, Thorbjørn, additional, Iversen, Lars, additional, Bonefeld, Charlotte Menné, additional, Grønbæk, Kirsten, additional, Met, Özcan, additional, Woetmann, Anders, additional, Ødum, Niels, additional, and Geisler, Carsten, additional
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- 2020
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18. MicroRNAs in the Pathogenesis, Diagnosis, Prognosis and Targeted Treatment of Cutaneous T-Cell Lymphomas
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Gluud, Maria, primary, Willerslev-Olsen, Andreas, additional, Gjerdrum, Lise Mette Rahbek, additional, Lindahl, Lise M., additional, Buus, Terkild B., additional, Andersen, Mads Hald, additional, Bonefeld, Charlotte Menne, additional, Krejsgaard, Thorbjorn, additional, Litvinov, Ivan V., additional, Iversen, Lars, additional, Becker, Jürgen C., additional, Persson, Jenny L., additional, Koralov, Sergei B., additional, Litman, Thomas, additional, Geisler, Carsten, additional, Woetmann, Anders, additional, and Odum, Niels, additional
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- 2020
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19. MicroRNA-93 Targets p21 and Promotes Proliferation in Mycosis Fungoides T Cells
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Gluud, Maria, primary, Fredholm, Simon, additional, Blümel, Edda, additional, Willerslev-Olsen, Andreas, additional, Buus, Terkild Brink, additional, Nastasi, Claudia, additional, Krejsgaard, Thorbjørn, additional, Bonefeld, Charlotte Menné, additional, Woetmann, Anders, additional, Iversen, Lars, additional, Litman, Thomas, additional, Geisler, Carsten, additional, Ødum, Niels, additional, and Lindahl, Lise M., additional
- Published
- 2020
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20. Staphylococcus aureus alpha-toxin inhibits CD8+ T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma
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Blümel, Edda, primary, Munir Ahmad, Shamaila, additional, Nastasi, Claudia, additional, Willerslev-Olsen, Andreas, additional, Gluud, Maria, additional, Fredholm, Simon, additional, Hu, Tengpeng, additional, Surewaard, Bas G. J., additional, Lindahl, Lise M., additional, Fogh, Hanne, additional, Koralov, Sergei B., additional, Rahbek Gjerdrum, Lise Mette, additional, Clark, Rachael A., additional, Iversen, Lars, additional, Krejsgaard, Thorbjørn, additional, Bonefeld, Charlotte Menné, additional, Geisler, Carsten, additional, Becker, Jürgen C., additional, Woetmann, Anders, additional, Andersen, Mads Hald, additional, Buus, Terkild Brink, additional, and Ødum, Niels, additional
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- 2020
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21. 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, primary, Krejsgaard, Thorbjørn, additional, Nastasi, Claudia, additional, Buus, Terkild Brink, additional, Nansen, Anneline, additional, Hald, Andreas, additional, Spee, Pieter, additional, Nielsen, Pia Rude, additional, Blümel, Edda, additional, Gluud, Maria, additional, Willerslev-Olsen, Andreas, additional, Woetmann, Anders, additional, Bzorek, Michael, additional, Eriksen, Jens O., additional, Ødum, Niels, additional, and Rahbek Gjerdrum, Lise Mette, additional
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- 2019
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22. Expression and function of Kv1.3 channel in malignant T cells in Sézary syndrome
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Hu, Tengpeng, primary, Buus, Terkild Brink, additional, Krejsgaard, Thorbjørn, additional, Nansen, Anneline, additional, Lundholt, Betina Kerstin, additional, Spee, Pieter, additional, Fredholm, Simon, additional, Petersen, David Leander, additional, Blümel, Edda, additional, Gluud, Maria, additional, Monteiro, Madalena N., additional, Willerslev-Olsen, Andreas, additional, Andersen, Mads Hald, additional, Straten, Per thor, additional, Met, Özcan, additional, Stolearenco, Veronica, additional, Fogh, Hanne, additional, Gniadecki, Robert, additional, Nastasi, Claudia, additional, Litman, Thomas, additional, Woetmann, Anders, additional, Gjerdrum, Lise Mette Rahbek, additional, and Ødum, Niels, additional
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- 2019
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23. 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, primary, Willerslev-Olsen, Andreas, additional, Gluud, Maria, additional, Lindahl, Lise M., additional, Fredholm, Simon, additional, Nastasi, Claudia, additional, Krejsgaard, Thorbjørn, additional, Surewaard, Bas G. J., additional, Koralov, Sergei B., additional, Hu, Tengpeng, additional, Persson, Jenny L., additional, Bonefeld, Charlotte Menné, additional, Geisler, Carsten, additional, Iversen, Lars, additional, Becker, Jürgen C., additional, Andersen, Mads Hald, additional, Woetmann, Anders, additional, Buus, Terkild Brink, additional, and Ødum, Niels, additional
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- 2019
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24. Antibiotics inhibit tumor and disease activity in cutaneous T cell lymphoma
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Lindahl, Lise M., primary, Willerslev-Olsen, Andreas, additional, Gjerdrum, Lise M.R., additional, Nielsen, Pia R., additional, Blümel, Edda, additional, Rittig, Anne H., additional, Celis, Pamela, additional, Herpers, Bjorn, additional, Becker, Jürgen C., additional, Stausbøl-Grøn, Birgitte, additional, Wasik, Mariusz A., additional, Gluud, Maria, additional, Fredholm, Simon, additional, Buus, Terkild B., additional, Johansen, Claus, additional, Nastasi, Claudia, additional, Peiffer, Lukas, additional, Kubat, Linda, additional, Bzorek, Michael, additional, Eriksen, Jens O., additional, Krejsgaard, Thorbjørn, additional, Bonefeld, Charlotte M., additional, Geisler, Carsten, additional, Mustelin, Tomas, additional, Langhoff, Erik, additional, Givskov, Michael, additional, Woetmann, Anders, additional, Kilian, Mogens, additional, Litman, Thomas, additional, Iversen, Lars, additional, and Odum, Niels, additional
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- 2019
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25. 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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26. 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.
- Subjects
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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27. Keratinocytes present Staphylococcus aureusenterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma
- Author
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Zeng, Ziao, Vadivel, Chella Krishna, Gluud, Maria, Namini, Martin R.J., Yan, Lang, Ahmad, Sana, Hansen, Morten Bagge, Coquet, Jonathan, Mustelin, Tomas, Koralov, Sergei B., Bonefeld, Charlotte Menne, Woetmann, Anders, Geisler, Carsten, Guenova, Emmanuella, Kamstrup, Maria R., Litman, Thomas, Gjerdrum, Lise-Mette R., Buus, Terkild B., and Ødum, Niels
- Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by malignant T-cells proliferating in a unique tumor microenvironment (TME) dominated by keratinocytes. Skin colonization and infection by Staphylococcus aureus(S. aureus) is a common cause of morbidity and suspected of fueling disease activity. Here we show that expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes correlates with IFN-γ expression in the TME. Importantly, IFN-γ induces HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. Likewise, preincubation of keratinocytes with supernatant from patient-derived SE-producing S. aureustriggers proliferation in malignant T-cells and cytokine release (including IL-2), when cultured with non-malignant T-cells. This is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. Furthermore, mutations in the HLA-DR binding sites of SE type-A, and siRNA-mediated knockdown of Janus Kinase-3 (JAK3) and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that, upon exposure to patient-derived S. aureusand SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureusmediated disease activity in CTCL.
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- 2024
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28. Staphylococcus aureusinduces drug resistance in cancer T cells in Sézary syndrome
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Vadivel, Chella Krishna, Willerslev-Olsen, Andreas, Namini, Martin R. J., Zeng, Ziao, Yan, Lang, Danielsen, Maria, Gluud, Maria, Pallesen, Emil M. H., Wojewoda, Karolina, Osmancevic, Amra, Hedebo, Signe, Chang, Yun-Tsan, Lindahl, Lise M., Koralov, Sergei B., Geskin, Larisa J., Bates, Susan E., Iversen, Lars, Litman, Thomas, Bech, Rikke, Wobser, Marion, Guenova, Emmanuella, Kamstrup, Maria R., Ødum, Niels, and Buus, Terkild B.
- Abstract
•Enterotoxins from S aureusbacteria induce drug resistance in primary malignant T cells in SS.•Targeting bacteria, their toxins, and downstream signaling pathways in malignant T cells abrogate the induction of drug resistance.
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- 2024
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29. Expression of the Voltage-Gated Potassium Channel Kv1.3 in Lesional Skin from Patients with Cutaneous T-Cell Lymphoma and Benign Dermatitis.
- Author
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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
- Subjects
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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30. Staphylococcus aureus alpha-toxin inhibits CD8+ T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma.
- Author
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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
- Subjects
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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31. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma.
- Author
-
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
- Subjects
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]- Published
- 2019
- Full Text
- View/download PDF
32. Single-cell heterogeneity in Sézary syndrome
- Author
-
Buus, Terkild Brink, primary, Willerslev-Olsen, Andreas, additional, Fredholm, Simon, additional, Blümel, Edda, additional, Nastasi, Claudia, additional, Gluud, Maria, additional, Hu, Tengpeng, additional, Lindahl, Lise M., additional, Iversen, Lars, additional, Fogh, Hanne, additional, Gniadecki, Robert, additional, Litvinov, Ivan V., additional, Persson, Jenny L., additional, Bonefeld, Charlotte Menné, additional, Geisler, Carsten, additional, Christensen, Jan Pravsgaard, additional, Krejsgaard, Thorbjørn, additional, Litman, Thomas, additional, Woetmann, Anders, additional, and Ødum, Niels, additional
- Published
- 2018
- Full Text
- View/download PDF
33. STAT5 induces miR-21 expression in cutaneous T cell lymphoma
- Author
-
Lindahl, Lise M., Fredholm, Simon, Joseph, Claudine, Nielsen, Boye Schnack, Willerslev-Olsen, Andreas, Gluud, Maria, Petersen, David L., Sibbesen, Nina, Hu, Tengpeng, Nastasi, Claudia, Persson, Jenny L., Mongan, Nigel P., Wasik, Mariusz A., Litvinov, Ivan V., Sasseville, Denis, Koralov, Sergei B., Bonefeld, Charlotte M., Geisler, Carsten, Woetmann, Anders, Ralfkiaer, Elisabeth, Iversen, Lars, and Odum, Niels
- Subjects
MiR-21, in situ, STAT5, IL-2, Cutaneous T-cell lymphoma (CTCL) - 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.
- Published
- 2016
34. Endolysin Inhibits Skin Colonization by Patient-Derived Staphylococcus Aureusand Malignant T-Cell Activation in Cutaneous T-Cell Lymphoma
- Author
-
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
- Abstract
Staphylococcus aureusis suspected to fuel disease activity in cutaneous T-cell lymphomas. In this study, we investigate the effect of a recombinant, antibacterial protein, endolysin (XZ.700), on S. aureusskin colonization and malignant T-cell activation. We show that endolysin strongly inhibits the proliferation of S. aureusisolated from cutaneous T-cell lymphoma skin and significantly decreases S. aureusbacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureusis profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureusinduction of IFNγand the IFNγ-inducible chemokine CXCL10in healthy skin. Whereas patient-derived S. aureusstimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving nonmalignant T cells, endolysin strongly inhibits the effects of S. aureuson activation (reduced CD25 and signal transducer and activator of transcription 5 phosphorylation) and proliferation (reduced Ki-67) of malignant T cells and cell lines in the presence of nonmalignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureusand blocks their potential tumor-promoting effects on malignant T cells.
- Published
- 2023
- Full Text
- View/download PDF
35. Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
- Author
-
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
- Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
- Published
- 2022
- Full Text
- View/download PDF
36. Staphylococcus Aureus Induces Stat5 Dependent Mir-155 Expression In Cutaneous T-Cell Lymphoma (Ctcl)
- Author
-
Willerslev-Olsen, Andreas, Rahbek Gjerdrum, Lise Mette, 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
- Abstract
Staphylococcus aureusenterotoxins (SE) are believed to fuel disease activity in cutaneous T-cell lymphoma (CTCL). Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sezary syndrome, the most common forms of CTCL. Yet, it remains incompletely characterized how SE fuel disease activity. Here, we show that SE induce expression of the oncogenic microRNA mir-155 in primary malignant T cells. Thus, SE and S. aureus-isolates from lesional patient skin induce mir-155 expression, at least partly, through the IL-2Rg/JAK/STAT5 pathway, and the effect is augmented by the presence of non-malignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus,express pY-STAT5, and display enhanced mir-155 expression, when compared with non-lesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased pY-STAT5 and mir-155 expression in lesional skin in two patients with Sezary syndrome. In conclusion, we demonstrate that S. aureusand its enterotoxins induce enhanced expression of oncogenic mir-155 providing mechanistic insight into the role of S. aureusin CTCL. Our findings support that environmental stimuli such as bacteria can fuel disease progression in CTCL.
- Published
- 2021
- Full Text
- View/download PDF
37. Staphylococcus aureusalpha-toxin inhibits CD8+T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma
- Author
-
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, Andersen, Mads Hald, Buus, Terkild Brink, and Ødum, Niels
- Abstract
ABSTRACTStaphylococcus aureusand 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 vivoby inhibiting CD8+T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with Staphylococcus aureusmay contribute to cancer immune evasion and disease progression in CTCL.
- Published
- 2020
- Full Text
- View/download PDF
38. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+T cells in cutaneous T-cell lymphoma
- Author
-
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
- Abstract
ABSTRACTStaphylococcus aureusis 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 aureusderived 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.
- Published
- 2019
- Full Text
- View/download PDF
39. Bio-O1-07 - miRNA signature in early-stage mycosis fungoides.
- Author
-
Sørensen, Sissel T, Litman, Thomas, Gluud, Maria, Celis, Pamela, Torres-Rusillo, Sara, Willerslev-Olsen, Andreas, Odum, Niels, Iversen, Lars, and Lindahl, Lise M
- Subjects
- *
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
- Full Text
- View/download PDF
40. MicroRNA-106b Regulates Expression of the Tumour Suppressors p21 and TXNIP and Promotes Tumour Cell Proliferation in Mycosis Fungoides.
- Author
-
Lindahl LM, Gluud M, Emmanuel T, Thomsen EA, Hu T, Rittig AH, Celis P, Stolearenco V, Krejsgaard T, Johansen C, Willerslev-Olsen A, Buus TB, Woetmann A, Aagaard L, Geisler C, Litman T, Mikkelsen JG, Odum N, and Iversen L
- Subjects
- Carrier Proteins, Cell Proliferation, Humans, Prognosis, MicroRNAs genetics, Mycosis Fungoides genetics, Skin Neoplasms genetics
- Abstract
A prognostic 3-miRNA classifier for early-stage mycosis fungoides has been developed recently, with miR-106b providing the strongest prognostic power. The aim of this study was to investigate the molecular function of miR-106b in mycosis fungoides disease progression. The cellular localization of miR-106b in mycosis fungoides skin biopsies was determined by in situ hybridization. The regulatory role of miR-106b was assessed by transient miR-106b inhibitor/mimic transfection of 2 mycosis fungoides derived cell lines, followed by quantitative real-time PCR (RT-qPCR), western blotting and a proliferation assay. MiR-106b was found to be expressed by dermal T-lymphocytes in mycosis fungoides skin lesions, and miR-106b expression increased with advancing mycosis fungoides stage. Transfection of miR-106b in 2 mycosis fungoides derived cell lines showed that miR-106b represses the tumour suppressors cyclin-dependent kinase inhibitor 1 (p21) and thioredoxin-interacting protein (TXNIP) and promotes mycosis fungoides tumour cell proliferation. In conclusion, these results substantiate that miR-106b has both a functional and prognostic role in progression of mycosis fungoides.
- Published
- 2020
- Full Text
- View/download PDF
41. Staphylococcus aureus alpha-toxin inhibits CD8 + T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma.
- Author
-
Blümel E, Munir Ahmad S, Nastasi C, Willerslev-Olsen A, Gluud M, Fredholm S, Hu T, Surewaard BGJ, Lindahl LM, Fogh H, Koralov SB, Rahbek Gjerdrum LM, Clark RA, Iversen L, Krejsgaard T, Bonefeld CM, Geisler C, Becker JC, Woetmann A, Andersen MH, Buus TB, and Ødum N
- Subjects
- Humans, Leukocytes, Mononuclear, Staphylococcus aureus, Bacterial Toxins, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Hemolysin Proteins, Lymphoma, T-Cell, Cutaneous immunology, Skin Neoplasms immunology
- Abstract
Staphylococcus aureus 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., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2020
- Full Text
- View/download PDF
42. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4 + T cells in cutaneous T-cell lymphoma.
- Author
-
Blümel E, Willerslev-Olsen A, Gluud M, Lindahl LM, Fredholm S, Nastasi C, Krejsgaard T, Surewaard BGJ, Koralov SB, Hu T, Persson JL, Bonefeld CM, Geisler C, Iversen L, Becker JC, Andersen MH, Woetmann A, Buus TB, and Ødum N
- 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., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2019
- Full Text
- View/download PDF
43. STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
- Author
-
Lindahl LM, Fredholm S, Joseph C, Nielsen BS, Jønson L, Willerslev-Olsen A, Gluud M, Blümel E, Petersen DL, Sibbesen N, Hu T, Nastasi C, Krejsgaard T, Jæhger D, Persson JL, Mongan N, Wasik MA, Litvinov IV, Sasseville D, Koralov SB, Bonefeld CM, Geisler C, Woetmann A, Ralfkiaer E, Iversen L, and Odum N
- Subjects
- Female, Humans, Lymphoma, T-Cell, Cutaneous genetics, Male, MicroRNAs genetics, STAT5 Transcription Factor genetics, Skin Neoplasms genetics, Gene Expression Regulation, Neoplastic physiology, Lymphoma, T-Cell, Cutaneous metabolism, MicroRNAs biosynthesis, STAT5 Transcription Factor metabolism, Skin Neoplasms metabolism
- 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., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
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