Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling

Lejeune, Diane; Demoulin, Jean‐Baptiste; Renauld, Jean‐Christophe

doi:10.1042/0264-6021:3530109

Cited by 19 publications

(11 citation statements)

References 39 publications

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“…Nevertheless, upregulation of SOCS3 has been reported in CTCL and other malignancies in association with elevated JAK-STAT signalling [35], and in JAK2V617F positive myeloproliferative disorders together with STAT3 and STAT5B [36], consistent with our findings. Although, SOCS3 has been reported as a feedback target of JAK-STAT signalling via IL9 in a mouse T-cell lymphoma [37], our unpublished findings discount a similar mechanism in MAC-1/2A/2B (Ehrentraut et al, in preparation). In CTCL cells SOCS3 overexpression inhibits apoptosis induced by interferon-α [38].…”

Section: Discussionsupporting

confidence: 48%

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

et al. 2013

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Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2–translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.

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Section: Discussionsupporting

confidence: 48%

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

et al. 2013

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“…STAT3 is an important member of the signaling pathway activated in IL9-producing cells. It is recruited upon IL9 binding to its receptor via its SH2 domain (26) and is crucial for apoptosis inhibition (27). More recently, its expression in Sézary syndrome cells has been attributed to a positive feedback loop of IL21 (19).…”

Section: Discussionmentioning

confidence: 99%

STAT3/5-Dependent IL9 Overexpression Contributes to Neoplastic Cell Survival in Mycosis Fungoides

Vieyra-Garcia

Wei

Naym

et al. 2016

Clinical Cancer Research

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Purpose Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9–producing T cells have been found in skin infections and certain inflammatory skin diseases, but their role in MF is currently unknown. Experimental Design We analyzed lesional skin from patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Results Malignant and reactive T cells produce IL9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous, whereas reactive T cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro. IL9-depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T cells, and activated CD4 and CD8 T lymphocytes. Conclusion Our results suggest that IL9 and its regulators are promising new targets for therapy development in mycosis fungoides.

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“…Transcriptionally, STATs are responsible for upregulation of Socs3 transcripts following cytokine stimulation. (Auernhammer et al 1999; Gatto et al 2004; He et al 2003; Lejeune et al 2001; Naka et al 1997). Recently, it has been demonstrated that other factors such as Specificity protein 3 (Sp3), c-Fos, c-Jun and FOXO3a and coactivators CREB-binding protein (CBP) and p300 are also involved in the transcriptional activation of Socs3 in a cytokine- and cell type-dependent manner (Barclay et al 2007; Ehlting et al 2005; Qin et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2

et al. 2009

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Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitin-ligase complex. Whether this regulation is relevant in primary cells is unknown. In this study, we utilized Socs2−/− mice to examine the role of SOCS2 in modulating SOCS3 expression and degradation, and its impact on IL-2 and IL-6 signalling in primary haemopoietic cells. Both biochemical and biological analyses demonstrated unperturbed SOCS3 expression and cytokine signalling in the absence of SOCS2. Our results suggest that SOCS2 is not a physiological regulator of SOCS3 expression and action in primary haemopoietic cells.

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Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling

Cited by 19 publications

References 39 publications

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

STAT3/5-Dependent IL9 Overexpression Contributes to Neoplastic Cell Survival in Mycosis Fungoides

Regulation of multiple cytokine signalling pathways by SOCS3 is independent of SOCS2

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