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Lymphoma

STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma

Leukemia volume 23, pages 1667–1678 (2009)Cite this article

Abstract

Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-γ, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-β (β isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.

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Acknowledgements

We are indebted to Véronique Debuysscher, Aline Regnier (Inserm E0351, Faculté de Médecine d'Amiens, France) and Sandrine Malot (Service d'Hématologie et de Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France) for technical assistance and Peter Moller for providing the protocol for the construction of the paraffin-embedded cell block. We also thank Christian Schmitt (Inserm U841, équipe 2, Créteil, France) for providing DERL-2, DERL-7 and SNK6 cell lines and for invaluable comments. Supported in part by a Grant from the GIS-Institut des Maladies Rares (GIS MR0428). This work was performed on behalf of the Clinphy Group.

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Author notes

  1. V Gouilleux-Gruart and Y Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Service d'Hématologie et de Thérapie Cellulaire, AP-HP, Hôpital Saint-Antoine, Paris, France

    P Coppo & N-C Gorin

  2. Université Pierre et Marie Curie (UPMC) Univ Paris 6, Paris, France

    P Coppo, C Perrot, P Dartigues & N-C Gorin

  3. Inserm U832, UPMC Univ Paris 06, Paris, France

    P Coppo, S Bouchet, L Douay & N-C Gorin

  4. Inserm U790, Villejuif, France

    P Coppo & H Bouamar

  5. Inserm U925, Laboratoire d'Immunologie, Faculté de Médecine, Amiens, France

    V Gouilleux-Gruart, H Bouhlal & K Lassoued

  6. Inserm U841, Créteil, France

    Y Huang & P Gaulard

  7. Université Paris 12, Créteil, France

    Y Huang & P Gaulard

  8. Département de Pathologie, AP-HP, Hôpital Henri Mondor, Créteil, France

    Y Huang & P Gaulard

  9. Unité de Cytogénétique onco-hématologique, AP-HP, Hôpital Saint-Antoine, Paris, France

    C Perrot

  10. Laboratoire d'Immunologie Cellulaire et Tissulaire, AP-HP, Groupe hospitalier la Pitié-Salpétrière, Paris, France

    V Vieillard

  11. Département de Pathologie, AP-HP, Hôpital Saint-Antoine, Paris, France

    P Dartigues

  12. Laboratoire de Virologie, UF7 EA3963, AP-HP, Hôpital Saint-Louis, Paris, France

    F Agbalika

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Coppo, P., Gouilleux-Gruart, V., Huang, Y. et al. STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma. Leukemia 23, 1667–1678 (2009). https://doi.org/10.1038/leu.2009.91

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