The inhibitory receptor Siglec-G controls the severity of chronic lymphocytic leukemia
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ABSTRACT:
PROVIDER: PRJNA946633 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23913000_1.fastq.gz | Fastqsanger.gz | |||
| SRR23913000_2.fastq.gz | Fastqsanger.gz | |||
| SRR23913100_1.fastq.gz | Fastqsanger.gz | |||
| SRR23913100_2.fastq.gz | Fastqsanger.gz | |||
| SRR23913001_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic Lymphocytic Leukaemia (CLL) is the most common leukemia in adults in the Western world. B cell receptor (BCR) signalling is known to be crucial for the pathogenesis and maintenance of CLL cells develop from mature CD5+ B cells. BCR signalling is regulated by the inhibitory co-receptor Siglec-G and Siglec-G-deficient mice have an enlarged CD5+ B1a cell population. Here, we determine how Siglec-G expression influences the severity of CLL.
2023-05-03 | GSE227678 | GEO
Project description:Chronic Lymphocytic Leukaemia (CLL) is the most common leukemia in adults in the Western world. B cell receptor (BCR) signalling is known to be crucial for the pathogenesis and maintenance of CLL cells which develop from mature CD5+ B cells. BCR signalling is regulated by the inhibitory co-receptor Siglec-G and Siglec-G-deficient mice have an enlarged CD5+ B1a cell population. Here, we determine how Siglec-G expression influences the severity of CLL. Our results show that Siglec-G deficiency leads to earlier onset and more severe course of the CLL-like disease in the murine Eµ-TCL1 model. In contrast, mice overexpressing Siglec-G on the B cell surface are almost completely protected from developing CLL-like disease. Furthermore, we observe a downmodulation of the human orthologue Siglec-10 from the surface of human CLL cells. These results demonstrate a critical role for Siglec-G in disease progression in mice, and suggest that a similar mechanism for Siglec-10 in human CLL may exist.
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Project description:Identification of human brain ligand for the microglial inhibitory receptors Siglec-3 (CD33) and Siglec-8
2022-03-07 | PXD032064 | JPOST Repository
Project description:Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role in pathogenesis. Targeting Siglec-8, an inhibitory receptor on MCs and eosinophils, has shown promising activity in preclinical and clinical studies. While the intracellular pathways that regulate Siglec-8 activity in eosinophils have been well studied, the signaling mechanisms that lead to MC inhibition have not been fully elucidated. Here, we evaluate the intracellular signaling pathways of Siglec‐8‐mediated inhibition in primary MCs using an anti‐Siglec‐8 monoclonal antibody (mAb). Phospho‐proteomic profiling of FcεRI‐activated MCs revealed Siglec-8 mAb-treatment globally inhibited proximal and downstream kinases, leading to attenuated MC activation and degranulation. In fact, Siglec‐8 was found to directly interact with FcεRI signaling molecules. Siglec‐8 inhibition was dependent on both cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact with the SH2 containing protein phosphatase Shp-2 upon Siglec-8 phosphorylation. Taken together, these data support a model in which Siglec-8 regulates proximal FcεRI‐induced phosphorylation events through phosphatase recruitment and interaction with FcεRI, resulting in global inhibition of MCs upon Siglec-8 mAb engagement.
2022-01-21 | PXD030820 | Pride
Project description:CD8+ T cells play a critical role in cancer immune-surveillance and pathogens elimination. However, the effector function of CD8+ T cells may be severely influenced due to inhibitory receptors. Here we identify Siglec-G as a coinhibitory receptor that plays a critical role in limiting the function of CD8+ T cells. Siglec-G is highly expressed on both human and murine tumor-infiltrating T cells, and SiglecG+ T cells enriched in the exhausted T cell subset. CD24-Siglec-G-SHP2 axis negatively regulates PI3K-AKT signaling and impairs metabolic reprogramming in CD8+ T cells and thereby dampens their activation, expansion and cytotoxicity. Genetic ablation of Siglec-G can enhance the efficacy of adoptively transferred T cells and CAR T cells to repress the growth of solid tumors. These results define a key role for Siglec-G in inhibiting CD8+ T cell-dependent responses, which strongly suggested its therapeutic effect in adoptive T cell therapy and tumor immunotherapy.
2024-12-18 | GSE255336 | GEO
Project description:Cancer immunotherapy targeting inhibitory receptors on T cells has changed the landscape of oncological practice, but most patients do not respond to current approaches. Thus, new targets on T cells for cancer immunotherapy are needed. CD33-related Siglecs are pattern recognition immune receptors binding to a broad range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) to dampen unwanted immune responses against self. Naïve T cells in humans have very low levels of inhibitory Siglec expression. Here, we show Siglec-9 in non-small cell lung cancer (NSCLC) are significantly upregulated on tumor-infiltrating T cells. These findings were confirmed in other tumor types including colorectal cancer, and ovarian cancer. Characterization of Siglec-9 expressing T cells showed a co-expression of inhibitory receptors including PD-1 and a distinct phenotype with increased cytokine production upon restimulation, compared to Siglec negative T cells. Functional analysis by reduction of sialoglycan-SAMPs on tumor cells in vitro and in vivo demonstrated an increased tumor cell killing and an inhibition of tumor growth. Overexpression of inhibitory Siglecs on T cells enhanced tumor growth in mice and exchange of inhibitory Siglecs on mouse T cells with an activating Siglec enhanced anti-cancer immunity. Increased T cell expression of Siglec-9 in NSCLC patients also correlated with survival, and analysis of Siglec-9 polymorphisms showed an association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as potential new target to improve T cell activation and cancer immunotherapy.
2018-12-26 | GSE115305 | GEO
Project description:Siglec-6 is a glycoprotein overexpressed on chronic lymphocytic leukemia (CLL) cell. We have shown that Siglec-6 promotes migration and adhesion of CLL cells towards CLL bone marrow stromal cells. To elucidate the mechanistic pathway involved in Siglec-6 dependent migration, we performed mass spectrometry proteomics analysis on MEC1-002 CLL cell line pulled down with a Siglec-6 targeted antibody, which revealed that Siglec-6 interacts with DOCK8, a guanine nucleotide exchange factor. Interaction of Siglec-6 with its ligand promotes DOCK8 dependent Cdc42 activation, WASP protein recruitment and F-actin polymerization. Therapeutically, Siglec-6 leukemic cells can be eliminated with a Siglec-6 targeted bispecific antibody in vitro and in vivo.
2024-05-08 | PXD039892 | Pride
Project description:Sialoglycan - Siglec axis has been reported to modulate the functions of multiple immune cell types. We found that inhibitory molecules human Siglec-9 and mouse Siglec-E both expressed at high level in tumor-infiltrating dendritic cells(DCs). Therefore, we generated mouse DC cell line lacking the expression of Siglec-E, and used bulk RNA sequencying to analyse how Siglec-E affects DC functions.
2022-03-23 | GSE190700 | GEO
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed
2016-03-16 | E-GEOD-79248 | biostudies-arrayexpress
Project description:Siglec-7 is a member of Siglec family of glycan recognition proteins involved in the regulation of natural killer (NK) cell activities. We found Siglec-7 ligand is highly expressed on JVM-3, a B cell chronic lymphocytic leukemia (B-CLL) cell line. In this experiment, we attempted at identifying the ligands of Siglec-7 on JVM-3 by applying the proximity labeling method we developed (Chang L et al., J Proteome Res. 2017, 16:3929-41).
2022-05-31 | PXD024690 | Pride