The effect of spleen tyrosine kinase on bone marrow monocytes in atherosclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205972 | GEO | 2023/07/20
REPOSITORIES: GEO
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Project description:The effect of spleen tyrosine kinase on bone marrow monocytes in atherosclerosis
| PRJNA848678 | ENA
Project description:This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL. B-cell leukemia samples (3) from a mutant mouse model were compared to sorted or cultured preB or proB cells from normal mice using Affymetrix GeneChip arrays.
2014-03-29 | E-GEOD-56345 | biostudies-arrayexpress
Project description:This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.
2014-03-29 | GSE56345 | GEO
Project description:Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.
2016-06-15 | PXD001680 | Pride
Project description:The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended.
| S-EPMC3985139 | biostudies-literature
Project description:The goal of this study is to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. We found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2-/-) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells by RNA seq. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression.
2022-07-20 | GSE203523 | GEO
Project description:We performed quantitative and qualitative proteomic analysis by nano LC-MS/MS to investigate global changes in the proteome of monocytes isolated from patients' peripheral blood by immunomagnetic separation. Cells were isolated from patients at different stages of non-related and chronic kidney disease-related atherosclerosis compared to healthy controls.
2024-01-23 | PXD041367 | Pride
Project description:Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP-deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggest IRE1 inhibition as a promising new way to counteract atherosclerosis.
2022-02-15 | PXD030594 | Pride
Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.
2011-05-03 | E-GEOD-29028 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.
| S-EPMC3589177 | biostudies-literature