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Growth Factors, Cytokines and Signal Transduction

Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells

Leukemia volume 15, pages 787–793 (2001)Cite this article

Abstract

Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Rαβγ) triggers mitogenesis in T cells. IL-2Rα expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells are IL-2Rα negative. An aberrant expression of IL-2Rα has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Rα expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant of CTCL. We show that (1) STAT3 (a transcription factor known to regulate IL-2Rα transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Rα gene; (3) the Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Rα mRNA and protein expression in parallel; and (4) tyrphostine AG490 inhibits IL-2 driven mitogenesis and triggers apoptosis in SS tumor cells. In conclusion, we provide the first example of a constitutive STAT3 activation in SS tumor cells. Moreover, our findings suggest that STAT3 activation might play an important role in the constitutive IL-2Rα expression, survival, and growth of malignant SS cells.

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Acknowledgements

The work described in this manuscript was performed at the Institute of Medical Microbiology and Immunology, Panum Institute, Building 22.5, University of Copenhagen, Blegdamsvej 3C, DK-2200 Copenhagen N, Denmark. This work was supported in part by the Leo Nielsen and wife Foundation (Direktør Leo Nielsen og Hustru Karen Margrethe Nielsens Legat for Lgevidenskabelig Grundforskning), the Danish Allergy Research Center, the Danish Research Councils, the Danish Biotechnological Center for Cellular Communication, the Novo Nordic Foundation, the Danish Medical Associations Research Foundation, the Danish Cancer Research Foundation (Dansk Kræftsforsknings Fond), The Danish Cancer Society (Kræftens Bekmpelse), Købmand i Odense Johann og Hanne Weimann f. Seedorff's Legat, the Carlsberg Foundation, the University of Copenhagen and the National Institute of Health (grant No. CA89194).

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Authors and Affiliations

  1. Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark

    KW Eriksen, G Mikkelsen, M Nielsen, C Geisler & N Ødum

  2. Institute of Human Genetics, University of Aarhus, Aarhus, Denmark

    K Kaltoft

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA

    Q Zhang & MA Wasik

  4. Institute of Medical Anatomy, University of Copenhagen, Copenhagen, Denmark

    MH Nissen & C Röpke

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Eriksen, K., Kaltoft, K., Mikkelsen, G. et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 15, 787–793 (2001). https://doi.org/10.1038/sj.leu.2402093

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