The oncogenic FIP1L1-PDGFR<b>α</b>fusion protein displays skewed signaling properties compared to its wild-type PDGFR<b>α</b>counterpart

Haan, Serge; Bahlawane, Christelle; Wang, Jiali; Nazarov, Petr V.; Muller, Arnaud; Eulenfeld, René; Haan, Claude; Rolvering, Catherine; Vallar, Laurent; Satagopam, Venkata; Sauter, Thomas; Wiesinger, Monique

doi:10.1080/21623996.2015.1062596

Cited by 5 publications

(5 citation statements)

References 74 publications

(94 reference statements)

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“…IL6 and OSM were shown to be present in inflammatory tumors. Inflammation has been established to be involved in cancer development, and constitutive activation of STAT3 found in many cancers is mediated by different mechanisms . In addition, IL6‐type cytokines have been shown to be essential players in the development of at least colon and liver cancers .…”

Section: Discussionmentioning

confidence: 99%

The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

Rolvering

Zimmer

Ginolhac

et al. 2018

Journal of Leukocyte Biology

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Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-γ-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-γ, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-γ. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other T 1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine pre-stimulation-mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation-induced cachexia-can be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD-L1 or/and IL6-type cytokines.

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Section: Discussionmentioning

confidence: 99%

The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

Rolvering

Zimmer

Ginolhac

et al. 2018

Journal of Leukocyte Biology

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“…Considering the molecular consequences of PDGFR gene fusions in clonal eosinophilia, enhanced phosphorylation of involved receptor tyrosine kinase could be regarded as a suitable clonal marker to differentiate between clonal and reactive eosinophilia. Besides, TKIs, which are the treatment of choice for clonal eosinophilia, could target this uncontrolled phosphorylation pathway 8,23 …”

Section: Discussionmentioning

confidence: 99%

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

et al. 2021

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Clonal eosinophilia is a hematologic disorder caused by translocation in growth factor receptor (GFR) genes. Despite the identified molecular mechanisms underlying clonal hypereosinophilia, the distinction between clonal and reactive eosinophilia has remained challenging due to the diversity of partner genes for translocated GFRs. This study aimed to examine the feasibility of phosphoflow cytometry in the diagnosis of clonal hypereosinophilia through evaluating the level of platelet‐derived growth factor receptor alpha (PDGFRA) phosphorylation and its correlation with PDGFRA genetic aberration. Blood samples were collected from 45 hypereosinophilia patients and 10 healthy controls. Using phosphoflow cytometry method, the phosphorylation state of PDGFRA was assessed. The specificity of phosflow results was confirmed by western blotting and eventually compared with qRT‐PCR expression analysis of 3′‐region of PDGFRA. To detect the genetic aberration of PDGFRA, 5′‐rapid amplification of cDNA ends (5′‐RACE) was performed. Phosflow analysis illustrated that 9 of 45 hypereosinophilic patients had higher level of PDGFRA phosphorylation while sequence analysis of 5′‐RACE‐PCR fragments confirmed that in seven cases of them, there was a PDGFRA‐FIP1L1 fusion. We also verified that two of nine patients with hyperposphorylated PDGFRA hold ETV6‐PDGFRA and STRN‐PDGFRA rearrangements. Importantly, nine cases also had significantly higher levels of PDGFRA mRNA expression when compared with healthy controls, and cases with no PDGFRA rearrangement. These findings highlight a robust correlation between hyperphosphorylation state of PDGFRA and aberrant PDGFRA gene fusions. This implicates phosflow as an efficient and reliable technique raising an intriguing possibility that it could replace other genomic and cDNA‐amplification‐based diagnostic approaches with limited effectiveness.

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“…Gene Expression analysis was performed using GeneChip Human Gene ST 2.0 arrays (Affymetrix). Quality control and data normalization were performed as previously reported [3], [7]. We focused on differentially expressed genes (DEG) across the mutants comparing with non-stimulated KIT-WT.…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Data on quantification of signaling pathways activated by KIT and PDGFRA mutants

et al. 2016

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The present data are related to the article entitled “Insights into ligand stimulation effects on gastro-intestinal stromal tumors signaling” (C. Bahlawane, M. Schmitz, E. Letellier, K. Arumugam, N. Nicot, P.V. Nazarov, S. Haan, 2016) [1]. Constitutive and ligand-derived signaling pathways mediated by KIT and PDGFRA mutated proteins found in gastrointestinal stromal tumors (GIST) were compared. Expression of mutant proteins was induced by doxycycline in an isogenic background (Hek293 cells). Kit was identified by FACS at the cell surface and found to be quickly degraded or internalized upon SCF stimulation for both Kit Wild type and Kit mutant counterparts. Investigation of the main activated pathways in GIST unraveled a new feature specific for oncogenic KIT mutants, namely their ability to be further activated by Kit ligand, the stem cell factor (scf). We were also able to identify the MAPK pathway as the most prominent target for a common inhibition of PDGFRA and KIT oncogenic signaling. Western blotting and micro-array analysis were applied to analyze the capacities of the mutant to induce an effective STATs response. Among all Kit mutants, only Kit Ex11 deletion mutant was able to elicit an effective STATs response whereas all PDGFRA were able to do so.

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The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

Cited by 5 publications

References 74 publications

The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies

Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients

Data on quantification of signaling pathways activated by KIT and PDGFRA mutants

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