Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNα

Brender, Christine; Lovato, Paola; Vh, Sommer; Woetmann, Anders; Am, Mathiesen; Geisler, Carsten; Wasik, Mariusz A.; Ødum, Niels

doi:10.1038/sj.leu.2403610

Cited by 75 publications

(70 citation statements)

References 37 publications

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“…Furthermore, no SOCS3-associated mutations have been identified in CTCL. 44 We also detected consistent expression of activated JAK1 and JAK2 in primary SS samples and demonstrate that downregulation of JAK1 and JAK2 expression using the P6 pan-JAK inhibitor results in significant downregulation of STAT3 expression in primary SS cells. Previous studies of a SS cell line and an MF patient sample ex vivo treated with a pan-JAK inhibitor AG490 also showed downregulation of activated STAT3.…”

Section: Discussionmentioning

confidence: 75%

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

et al. 2011

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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 Sé zary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4 þ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylationspecific 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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Section: Discussionmentioning

confidence: 75%

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

et al. 2011

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“…Indeed, reports describing SOCS-3 hypermethylation and subsequent loss of expression in a variety of cancers support the idea that SOCS-3 may have a tumor-suppressing function (94)(95)(96)(97). In contrast, elevated SOCS-3 expression was reported in human breast cancer and melanoma tissues, as well as in a subset of classic Hodgkin's lymphoma cell lines and primary lymphoma cells (98)(99)(100)(101)(102)(103)(104). In several studies, SOCS-3 promoted cell growth and proliferation in a number of cancers (100,103,105), and elevated levels of SOCS-3 were reported to confer a growth advantage to a melanoma cell line (103).…”

Section: Involvement Of Socs-3 In Gliomasmentioning

confidence: 90%

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

Brantley

Benveniste

2008

Molecular Cancer Research

212

159

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“…[23][24][25] In advanced disease, malignant T cells display a cytokine-independent, constitutive activation of JAK3, which drives a constitutive activation of STAT3 that, in turn, increases survival and resistance to apoptosis in malignant T cells, 26,27 and induces production of cytokines involved in eosinophilia and erythroderma (IL-5), as well as T helper 2 (Th2), 28 and Th17 29 cytokines. Furthermore, the pathway is believed to play a role in creating a pro-oncogenic inflammatory environment via production of VEGF 30 and IL-10 31 and induction of suppressor of cytokine signaling-3 (SOCS-3), 32 which confers resistance to IFNα in malignant T cells. Interestingly, miR-21, another oncogenic miRNA that is significantly upregulated in CTCL patients, 17,18 was shown to be modulated by STAT3.…”

Section: Resultsmentioning

confidence: 99%