title: Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1.
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.
authors.affiliation: Skin Tumour Unit, St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: R C T
authors.initials: RC
authors.lastname: McKenzie
authors.forename: C L
authors.initials: CL
authors.lastname: Jones
authors.forename: I
authors.initials: I
authors.lastname: Tosi
authors.forename: J A
authors.initials: JA
authors.lastname: Caesar
authors.forename: S J
authors.initials: SJ
authors.lastname: Whittaker
authors.forename: T J
authors.initials: TJ
authors.lastname: Mitchell
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D019175:DNA Methylation; D017931:DNA Primers; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012751:Sezary Syndrome / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6