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Lymphoma

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

Leukemia volume 26, pages 323–331 (2012)Cite this article

Abstract

Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sézary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4+ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylation-specific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

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Acknowledgements

We thank Ms Silvia Ferreira for providing expert technical assistance. This work was supported by grants from the British Skin Foundation (RCTM), Guy's and St Thomas' Charitable Foundation and includes support from the ‘Skin Matters’ fund (CLJ). Support from Guy's & St Thomas' NHS Foundation (TJM) is gratefully acknowledged. We acknowledge the financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre ward to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust.

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  1. Division of Genetics and Molecular Medicine, Skin Tumour Unit, St John's Institute of Dermatology, King's College London, London, UK

    R C T McKenzie, C L Jones, I Tosi, J A Caesar, S J Whittaker & T J Mitchell

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McKenzie, R., Jones, C., Tosi, I. et al. Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1. Leukemia 26, 323–331 (2012). https://doi.org/10.1038/leu.2011.198

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