ITK-SYK induced peripheral T-cell lymphomas induce granulocyte activation
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PROVIDER: PRJNA917510 | ENA |
REPOSITORIES: ENA
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Project description:ITK-SYK or control vector were overexpressed in Balb/c mice and ITK-SYK mice developed peripheral T-cell lymphomas within 5 weeks. CD4+ T-cells and granulocytes were harvested from the spleens of control and ITK-SYK mice and compared.
2025-01-10 | GSE222050 | GEO
Project description:IL-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T-cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently FDA approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent catalytic inhibitor, blocked the activation of NF-kB/GATA-3 signaling and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
2023-05-29 | PXD040668 | Pride
Project description:IL-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T-cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently FDA approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non- covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS- 509744, blocked the activation of NF-kB/GATA-3 signaling and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
2023-03-01 | GSE226136 | GEO
Project description:Regulatory T cells (Tregs) play a critical role in controlling autoimmunity and limiting tissue destruction and inflammation. IL2-inducible T cell kinase (Itk) belongs to the Tec family of tyrosine kinases and is an important component of TCR-mediated signaling. Here we showed that either genetic ablation of Itk signaling, or inhibition of Itk signaling pathways resulted in increased frequency of “noncanonical” CD4+CD25−FoxP3+ Tregs (ncTregs), as well as of “canonical” CD4+CD25+FoxP3+ Tregs (canTregs). Using in vivo models, we showed that ncTregs can prevent the development of acute graft-versus-host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft-versus-leukemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk-/- ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse cells and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders
2021-10-19 | GSE185327 | GEO
Project description:Among B-cell lymphomas mantle cell lymphoma (MCL) has the worst prognosis. By using a combination of genomic and expression profiling (Affymetrix GeneChip Mapping 10k Xba131 and U133 set), we analysed 26 MCL samples to identify genes relevant to MCL pathogenesis and that could represent new therapeutic targets. Recurrent genomic deletions and gains were detected. Genes were identified as overexpressed in regions of DNA gain on 3q, 6p, 8q, 9q, 16p and 18q, including the cancer genes BCL2 and MYC. Among the transcripts with high correlation between DNA and RNA, we identified SYK, a tyrosine kinase involved in B-cell receptor signalling. SYK was amplified at DNA level, as validated by fluorescence in situ hybridisation (FISH) analysis, and overexpressed at both RNA and protein levels in the JeKo-1 cell line. Low-level amplification, with protein overexpression of Syk was demonstrated by FISH in a small subset of clinical samples. After treatment with low doses of the Syk inhibitor piceatannol, cell proliferation arrest and apoptosis were induced in the cell line overexpressing Syk, while cells expressing low levels of Syk were much less sensitive. A combination of genomic and expression profiling suggested Syk inhibition as a new therapeutic strategy to be explored in lymphomas. Keywords: cell type comparison
2006-02-08 | GSE4176 | GEO
Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk.
2009-05-20 | GSE12464 | GEO
Project description:ITK Degradation to Block T-cell Receptor Signaling and Overcome Therapeutic Resistance in T-Cell Lymphomas
| PRJNA938918 | ENA
Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk. Experiment Overall Design: CD3+ T-cells from pooled suspensions of spleen and lymph nodes of Wt and Itk knockout mice on C57BL/6 background were isolated after negative depletion. Unstimulated as well as stimulated T-cells were studied. Stimulations were done with anti-CD3 (1 mg/ml) with or without anti-CD28 (3 mg/ml) in the presence or absence of CsA (1 mg/ml) for 24 hrs. For each stimulus, at least duplicate samples were used.
2009-05-29 | E-GEOD-12464 | biostudies-arrayexpress
Project description:We analyzed gene expression profiles of unstimulated Herpesvirus Saimiri (HVS) transformed T cells (CD4+) of patients harboring a homozygous R335W mutation in the IL-2 inducible T cell kinase (ITK) compared to healthy control HVS cells. We identified a set of 1927 Affymetrix probe sets showing significant misregulation in the ITK deficient cells (Welch's T-test, p<0.05). HVS T cell lines (ITK wt or ITK R335W, each CD4+) from three independent culturing time points were used for RNA extraction and hybridization on Affymetrix microarrays.
2011-12-20 | E-GEOD-28200 | biostudies-arrayexpress
Project description:To dissect T cell lymphoma pathogenesis, we previously engineered a genetically controllable murine model of human T-NHL based on tamoxifen-inducible irreversible expression of the T-NHL oncogene ITK-SYK, which enforces strong oncogenic TCR signaling. Three days after ITK-SYK expression, we purified the oncogene-expressing cells by fluorescence-activated cell sorting (FACS) for RNA sequencing.
2023-08-08 | GSE212832 | GEO