CTCL is the most frequent primary lymphoma of the skin

Patients diagnosed in early stages often experience an indolent disease course and have a favorable prognosis. Yet, the disease follows an aggressive course in a substantial fraction (15–20%) of patients and despite recent progress in novel therapies, advanced disease remains a major challenge as relapses are common and cure is rare.

CTCL plaque schematic

Recently, it was discovered, and independently confirmed in a meta-analysis study, that malignant T cells in the majority of patients display ectopic expression of the B-lymphoid tyrosine kinase (Blk), a member of the Src kinase family. Importantly, gene knockdown experiments showed that Blk promoted the proliferation of malignant T cells from CTCL patients,2 suggesting that Blk—in analogy with other Src family members—may function as an oncogene.

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Malignant Cutaneous T-Cell Lymphoma Cells Express IL-17 Utilizing the Jak3/Stat3 Signaling Pathway

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.

IL-17

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 b 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.

CD22 splice forms in CTCL article image

Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from CTCL patients

Ieva Bagdonaite, Hans H. Wandall, Ivan V. Litvinov, Claudia Nastasi, Jürgen C. Becker, Sally Dabelsteen, Carsten Geisler, Charlotte M. Bonefeld, Qian Zhang, Mariusz A. Wasik, Youwen Zhou, Denis Sasseville, Niels Ødum and Anders Woetmann

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BLK - an oncogene in CTCL.pdf article image

B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target for therapy with dasatinib in CTCL

DL Petersen, T Krejsgaard, J Berthelsen, S Fredholm, A Willerslev-Olsen, NA Sibbesen, CM Bonefeld, MH Andersen, C Francavilla, JV Olsen, T Hu, M Zhang, MA Wasik, C Geisler, A Woetmann and N Odum

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IL-17 is driven by STAT3 in malignant T cells article image

Malignant Cutaneous T-Cell Lymphoma Cells Express IL-17 Utilizing the Jak3/Stat3 Signaling Pathway

Thorbjørn Krejsgaard, Ulrik Ralfkiaer, Erik Clasen-Linde, Karsten W. Eriksen, Katharina L. Kopp, Charlotte M. Bonefeld, Carsten Geisler, Sally Dabelsteen, Mariusz A. Wasik, Elisabeth Ralfkiaer, Anders Woetmann, and Niels Odum

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Acknowledgements

This work was supported research funding from the Danish Cancer Society, the Carlsberg Foundation, Dansk Kræftforsknings Fond, the Danish Research Councils, the Danish National Advanced Technology Foundation (Innovationsfunden), the Lundbeck Foundation, the Novo Nordic Foundation, Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, the Cutaneous Lymphoma Foundation, the Neye Foundation, the Beckett Foundation (Beckett-Fonden), the Canadian Dermatology Foundation, the the Le Fonds de recherche du Québec - Santé (research grants to Dr. Sasseville), Fight Cancer Program (Knæk Cancer Programmet), the University of Copenhagen, and the National Cancer Institute (grant CA89194, M.A.W.).

Finally, we thank K. Kaltoft for providing us with the MySi, MyLa2059 and SeAx cell lines and Dr. Thomas Kupper from Harvard University for generously providing cDNA samples from CTCL patients for RT-PCR analysis.