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Gene expression profiling of five diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4, DHL6, LY7, HBL1 and U2932, treated with the SYK inhibitor, R406

ABSTRACT: The five DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43510 | GEO | 2013/08/31

SECONDARY ACCESSION(S): PRJNA186620

REPOSITORIES: GEO

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Gene expression profiling of five diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4, DHL6, LY7, HBL1 and U2932, treated with the SYK inhibitor, R406

Project description:The five DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK. RNA samples from five DLBCL cell lines treated with R406 or vehicle (DMSO) alone for 0, 6, or 24 hours were profiled in triplicate on Affymetrix HT_HG-U133plust2 chips.

2013-08-31 | E-GEOD-43510 | biostudies-arrayexpress

Gene expression profiling of two diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4 and DHL6, treated with the SYK inhibitor, R406

2013-12-31 | GSE34176 | GEO

Gene expression profiling of two diffuse large B-cell lymphoma (DLBCL) cell lines, DHL4 and DHL6, treated with the SYK inhibitor, R406

Project description:The two DLBCL cell lines were treated with R406 to assess the signature of SYK inhibition. In previous studies, R406 decreased the proliferation and induced apoptosis of these surface Ig+ cell lines. In the previous studies, R406 inhibited the autophosphorylation of SYK 525/526 and SYK-dependent phosphorylation of BCR signaling components such as BLNK. RNA samples from two DLBCL cell lines, DHL4 and DHL6, treated with R406 or vehicle (DMSO) alone for 0, 2, 6, 24 or 48 hours were profiled in triplicate on Affymetrix HT_HG-U133A chips.

2013-12-31 | E-GEOD-34176 | biostudies-arrayexpress

BLNK negatively regulates C-type lectin receptor-mediated antifungal immunity through inhibiting macrophage migration

Project description:B cell linker protein (BLNK) is a pivotal adaptor protein that interfaces the B cell receptor (BCR)-associated spleen tyrosine kinase (Syk) to regulate B cell function and development. However, it is still not well understood whether BLNK is involved in Syk-coupled C-type lectin receptor (CLR) signaling in myeloid cells, particularly in the context of antifungal immunity. Here, we show that stimulation with fungi-derived β-glucans or α-mannans induced the phosphorylation of BLNK in macrophages, which was significantly impaired due to the deficiency of CLRs including Dectin-1 and Dectin-2, as well as their downstream mediators Syk and Fc-receptor gamma-chain (FcRγ). Furthermore, BLNK is induced to be interacted with casitas B-lineage lymphoma (c-Cbl), which is completely dependent on the engagement of Dectin-1 and Dectin-2. Notably, BLNK deficiency facilitates CLR-mediated recruitment of c-Cbl/phosphatidylinositol 3-kinase (PI3K) complex to F-actin cytoskeleton, thereby promoting macrophage migration. Consequently, mice with monocyte-specific deficiency of BLNK are highly resistant to the infection with Candida albicans, a major human fungal pathogen, through increasing the infiltration of Ly6C+macrophages into kidneys. Together, our data indicate that BLNK functions downstream of Syk-coupled CLRs to negatively regulate antifungal immunity against C. albicans infection. These findings unravel a previously unidentified role of BLNK that negatively regulates macrophage migration through inhibiting CLR-mediated recruitment of c-Cbl/PI3K complex to the cytoskeleton.

2023-11-07 | GSE246891 | GEO

R406-Inhibition of Syk-Cn-NFAT Signaling Axis Promotes Chemical Reprogramming via Metabolic Rewiring and H2S Production

Project description:Small molecules not only are convenient and useful for controlling cell fates, but also can provide better understanding of the molecular mechanisms of cell-fate transitions. Here, we identified that spleen tyrosine kinase (Syk) inhibitor R406 could significantly promote the early stage of mouse chemical reprogramming. Furthermore, R406 alleviated the Syk-calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling cascade-mediated suppression of glycine, serine and threonine metabolic genes transcriptionally, which is previously unrecognized. In turn, R406 upregulated metabolites of glycine, serine and threonine metabolism and downstream transsulfuration cysteine biosynthesis pathway and cysteine metabolism. Subsequently, increased cellular hydrogen sulfide (H2S) after R406 treatment downregulated oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS), modulated redox homeostasis, and significantly enhanced chemical reprogramming. In sum, our studies have not only improved the chemical reprogramming technique, but also identified interesting molecular mechanisms of chemical-induced pluripotent reprogramming, which hold great potentials in regenerative medicine.

2021-03-14 | GSE154687 | GEO

SYK activity modulates the EGFR-dependent transcriptome

Project description:Background: Among all gynecologic malignancies, epithelial ovarian cancer has the highest case-to-fatality ratio. Most patients are diagnosed at advanced stages and recurrence is common and accounts for disease-related mortality. Spleen tyrosine kinase (SYK) is an emerging cancer-associated kinase upregulated in recurrent tumors and is amenable for inhibition using small compounds that have been studied in clinical trials for autoimmune diseases. Our previous proteomic analysis identified several novel SYK substrates including EGFR and ERBB2. Here, we investigated the cross-talk between these pathways in ovarian carcinomas. Methods: Immunohistochemistry and immunoblotting were utilized to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq to investigate the SYK-regulated EGF-induced transcriptome. Results: Intense immunoreactivity of active pSYK(Y525/526) correlated with poor overall survival in two independent ovarian cancer cohorts. SYK directly phosphorylated EGFR and ERBB2, while knockout of SYK reduces their phosphorylation. Phosphorylation levels of SYK(Y525/526) positively correlated with EGFR(Y1187) and STAT3(Y705). Active SYK reduced sensitivity to the EGFR/ERBB2 inhibitor, lapatinib, and SYK non-phosphorylatable EGFR mutant was more sensitive to paclitaxel. SYK modulated the EGF-induced transcriptome, supporting its involvement in EGFR/ERBB2-regulated transcriptional activity. Conclusions: Our findings suggest an upstream role of SYK in regulating the EGFR/ERBB2 signaling, and provide a biological rationale for targeting SYK in ovarian cancer therapy.

2020-11-08 | GSE106716 | GEO

Dectin-1-mediated signaling leads to characteristic gene expressions in rat mast cells

Project description:Rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Dectin-1-mediated activation and responses of mast cells. Dectin-1-mediated signaling stimulated characteristic gene expression, such as MCP-1, IL-4, IL-13, TNF-αand Nfkbiz. RBL-2H3 cell line stably expressing Dectin-1 was established. Non-stimulated cells (control) compared to Dectin-1-stimulated (Curdlan) cells in order to comfirm Dectin-1-mediated signaling-inducible genes. Dectin-1-stimulated cells compared to Syk inhibitor R406-pretreated cells in order to examine the importance of Syk for Dectin-1-mediated gene up-regulations.

2014-03-27 | E-GEOD-56246 | biostudies-arrayexpress

C/EBPb cooperates with BLNK mutation in preB leukemogenesis (BLNK2)

Project description:BLNK (BASH/SLP-65) encodes an adaptor protein within the B-cell receptor signaling. Loss-of-function mutations of BLNK are observed in human preB-ALL, and a subset of Blnk knock-out mice develop preB-ALL. To understand the molecular mechanism of preB-ALL development associated with the Blnk mutation, retroviral tagging was applied on Blnk KO mice using Moloney murine leukemia virus (MoMLV). The Blnk mutation significantly accelerated the disease onset of MoMLV-induced leukemia and increased the incidence of preB-ALL. Cebpb was identified as the most frequent common retroviral integration site, suggesting that Cebpb upregulation cooperates with Blnk mutation. Transgenic expression of the LAP (liver-enriched activator protein) isoform of C/EBP-beta significantly accelerated preB-ALL development of Blnk ko mice. We used microarrays to detail the global program of gene expression in mouse preB-ALL

2021-10-27 | GSE110738 | GEO

C/EBPb cooperates with BLNK mutation in preB leukemogenesis (BLNK1)

2021-10-27 | GSE110737 | GEO

In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

Project description:We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. R940406 (R406, the active metabolite of fostamatinib) was supplied by Rigel Pharmaceuticals, Inc., South San Francisco, CA, and AstraZeneca Pharmaceuticals, Wilmington, DE, USA. R406 was resuspended in dimethyl sulfoxide (DMSO) (Sigma-Aldrich) and stored at −80°C. . HL-60, U937 and KG-1 cell lines were purchased from the American Type Culture Collection. MOLM-14 cell lines were provided by Dr. Scott Amstrong (Dana-Farber Cancer Institute, Boston MA, USA.) All cell lines were maintained in RPMI 1640 (Cellgro) supplemented with 1% penicillin-streptomycin and 10% fetal bovine serum (FBS, Sigma-Aldrich) at 37 °C with 5% CO2.

2013-04-24 | GSE46302 | GEO

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