Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma

Guiter, Chrystelle; Dusanter‐Fourt, Isabelle; Copie‐Bergman, Christiane; Boulland, Marie-Laure; Gouvello, Sabine Le; Gaulard, Philippe; Leroy, Karen; Castellano, Flavia

doi:10.1182/blood-2003-10-3545

Cited by 178 publications

(133 citation statements)

References 37 publications

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“…Thus, IL-4 may antagonize anti-IgM-mediated death signals that converge on the mitochondrion, by suppressing the pro-apoptotic function of BAD and by increasing Bcl-xL beyond a minimal threshold. The activation of all signaling pathways by IL-4 is dependent on the activation of JAK family members and, indeed, we found that AG490, an extensively utilized, selective JAK inhibitor [50], abrogated the ability of IL-4 to protect CH31 cells from anti-IgM-induced apoptosis ( Figure 7A). The IL-4-induced activation of the IRS2/PI-3K pathway plays a significant role in the protection of [11,51].…”

Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protementioning

confidence: 68%

“…Indeed, high IL-4 levels have been associated with reduced apoptosis of non-Hodgkin's lymphoma [55]. Interestingly, primary mediastinal large B-cell lymphomas (PMBL) have been shown to contain constitutive activation of STAT6 without evidence of cytokine production [50]. On the other hand, classical Hodgkin's lymphoma Reed-Sternberg cells produce IL-13 and display IL-13-dependent STAT6 activation and enhanced survival [14].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, classical Hodgkin's lymphoma Reed-Sternberg cells produce IL-13 and display IL-13-dependent STAT6 activation and enhanced survival [14]. These effects are thought to be regulated by the STAT6-mediated induction of Bcl-xL [14,50,55]. In contrast, IL-4 was able to substantially protect B cells isolated from STAT6-deficient animals from spontaneous apoptosis [13,15], indicating the contribution of another signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Carey

Семенова

et al. 2007

Cell Res

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Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase (PI-3K) signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis. In this study, we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31, a model B-cell lymphoma line. In CH31, anti-IgM treatment leads to the loss of mitochondrial membrane potential, phospho-Akt, phospho-CDK2, and c-myc protein. These losses are followed by massive induction of p27 Kip1 protein expression, cell cycle arrest, and apoptosis. Strikingly, IL-4 treatment prevented or reversed these changes. Furthermore, IL-4 suppressed the activation of caspases 9 and 3, and, in contrast to previous reports, induced the phosphorylation (deactivation) of BAD. IL-4 treatment also induced expression of BclxL, a STAT6-dependent gene. Pharmacologic inhibitors and dominant inhibitory forms of PI-3K and Akt abrogated the anti-apoptotic function of IL-4. These results suggest that the IL-4 receptor activates several signaling pathways, with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.

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Section: Effects Of Il-4 Signaling On the Pi-3k/akt Pathway And Protementioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

Carey

Семенова

et al. 2007

Cell Res

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“…In human disease, this hypothesis is difficult to demonstrate compared to a specific and recurrent mutation. Nevertheless, JAK2 overexpression was described in primary mediastinal large B-cell lymphoma and might explain the constitutive STAT6 activation (Guiter et al, 2004). Moreover, amplification of the JAK2 gene was observed in Hodgkin's lymphoma (Joos et al, 2000(Joos et al, , 2003, were STAT3 and STAT5 are often phosphorylated (Kube et al, 2001;Cochet et al, 2006), and in some cases of acute myeloid leukemia (Rucker et al, 2006).…”

Section: Activated Signaling Pathways In Autonomous Clonesmentioning

confidence: 99%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokineindependent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.

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“…DNA sequences are numbered in relation to the start codon as 1, and the corresponding protein sequences are shown. and has been reported for several lymphomas including PMBL and classical Hodgkin lymphoma (cHL) (Kube et al, 2001;Skinnider et al, 2002;Guiter et al, 2004). PMBL is a rare disease with characteristic features Figure 2 for caption refer to page 2682 SOCS-1 mutations in classical Hodgkin lymphoma MA Weniger et al distinguishing it from other types of diffuse large B-cell lymphoma (Barth et al, 2002), however, there is increasing evidence of a relatedness to the far more frequent cHL.…”

mentioning

confidence: 99%

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

et al. 2006

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The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/ STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in lasermicrodissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (Po0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.

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Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma

Cited by 178 publications

References 37 publications

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

JAK kinases overexpression promotes in vitro cell transformation

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

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