Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of SOCS1 overexpression on AML gene expression in OCI-AML2 cell line

ABSTRACT: Despite the curative potential of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML), its efficacy is limited by intrinsic resistance of cancer cells to donor-derived T-cell cytotoxicity. Using a genome-wide CRISPR screen, we identified the SOCS1-JAK1-STAT1 pathway as a mediator of AML susceptibility to T cells. SOCS1 knockdown in AML cells sensitized them to killing by allogeneic T cells, whereas SOCS1 overexpression in AML cells induced resistance to T-cell anti-leukemic activity. Mechanistically, SOCS1 protected AML cells from T-cell killing by antagonizing IFNγ-JAK1-induced ICAM-1 expression. Furthermore, primary AML cells with lower SOCS1 expression correlated with better overall survival in patients, especially those with a lower exhausted CD8+ T-cell score. Thus, this study reveals SOCS1 and its downstream mediators as a potential targetable pathway to enhance T cell-based immunotherapy for AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288632 | GEO | 2025/02/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SOCS1

Project description:SOCS1

| PRJNA647451 | ENA

The tumor suppressor SOCS1 diminishes tolerance to oxidative stress in hepatocellular carcinoma

Project description:SOCS1 is a tumor suppressor in hepatocellular carcinoma. Recently we showed that loss of SOCS1 in hepatocytes promotes NRF2 activation. Here we investigated how SOCS1 expression affected oxidative stress response in HCC cells. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). Induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed increased induction of reactive oxygen species (ROS) but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. Proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways including those implicated in mitochondrial ROS generation and detoxification by peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.

2024-05-22 | PXD047908 | Pride

SILAC-based quantitative proteomics implicates SOCS1 in modulating protein constituents of large macromolecular complexes in hepatocytes

Project description:Suppressor of Cytokine Signaling 1 (SOCS1) functions as a tumor suppressor in hepatocellular carcinoma by regulating cytokine, growth factor and other signaling pathways. The tumor suppressor functions of SOCS1 are mediated partly via promoting ubiquitination and proteasomal degradation of several signaling proteins. In this study, we used an unbiased approach to characterize SOCS1-mediated changes in the protein profile of hepatocytes. The murine HCC cell line Hepa1-6 transduced with wildtype SOCS1, an SH2 domain mutant or the empty lentiviral vector were grown in Stable Isotopic Labelling of Amino acids in Cell culture (SILAC) media. The cells were stimulated with hepatocyte growth factor or left at steady state. Following cell lysis, proteins were separated on SDS-PAGE gels and peptides extracted by in-gel trypsinization were analyzed by mass spectrometry. Differentially modulated proteins identified and quantified were subjected to pathway enrichment analysis. In total, 3440 proteins were identified in Hepa cells in the presence of SOCS1 at steady state, of which 181 proteins were significantly modulated by SOCS1. The SH2 domain mutation and HGF stimulation increased the number of differentially modulated proteins, which showed only a limited overlap with SOCS1-modulated proteins. Protein interaction network analysis revealed enrichment of SOCS1-modulated proteins within multiprotein complexes such as ubiquitin conjugating enzymes, proteasome, mRNA spliceosome, mRNA exosome and mitochondrial ribosome. Further analysis indicated SOCS1-dependent regulation of the UBE2D ubiquitin conjugating enzymes, which are implicated in growth factor receptor signaling, indirectly via an unknown protein. Given the ubiquitous and highly regulated induction of SOCS1 by diverse cellular stimuli, our findings suggest a fundamental role of SOCS1 in regulating large macromolecular complexes that are important for cellular homeostasis.

2021-02-01 | PXD019135 | Pride

Impact of SOCS1 inactivation on Marilyn adoptive cell transfer in MB49 female C57BL/6 bearing mice

Project description:In vivo, the expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using an in vivo genome-wide CRISPR-Cas9 screen, we identified SOCS1 as a major non-redundant checkpoint imposing a brake on antigen experienced CD4+ T-cell proliferation upon antigen challenge. Although SOCS1 has been previously described as an inhibitor of CD8+ T-cell effector function, we highlight here that it is abrogating the CD4+ T-cell response. SOCS1 integrates several cytokines receptor signals to actively silence TCR-induced polycytokine signaling pathways, restraining CD4+ T cell proliferation and functions. Targeting SOCS1 in mouse and human CD4+ and CD8+ T cells improved the therapeutic efficacy of antitumor adoptive T-cell therapies, enhancing intra-tumor T cell accumulation, persistence and effector functions. SOCS1 deletion in CAR-T cells enhances CD4+ CAR T-cell proliferation/survival and polyfunctionality in vivo, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of re-stimulated CD4+ T cells, opening new possibilities to optimize adoptive T cell therapies.

2021-09-02 | GSE154791 | GEO

Whole-genome expression analysis in IFNgamma stimulated bone marrow-derived macrophages from transgenic mice expressing only non-nuclear mutant Socs1

Project description:To study the role of SOCS1 in the cell nucleus in vivo, we generated a transgenic mouse model using a bacterial artificial chromosome (BAC) containing a mutated Socs1 locus (non-nuclear Socs1ÎNLS), GFP and firefly Luciferase, termed MGL. MGL transgenic mice expressing only non-nuclear mutant Socs1 (Socs1-/- MGLtg mice) survive the early lethal phenotype of Socs1-/- mice that die within 3 weeks due to excessive immune signaling, mainly depending on hyperresponsiveness to IFNgamma. Therefore, we suggested that classical IFNgamma signaling might still be efficiently regulated by SOCS1ÎNLS. To prove this hypothesis, bone marrow-derived macrophages (BMMs) from Socs1-/- MGLtg mice and the control group (Socs1+/- MGLtg mice) were stimulated with IFNgamma for 24 h and subjected to whole-genome expression analysis.

2016-11-10 | E-MTAB-4938 | biostudies-arrayexpress

Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens [TIL5746_human_invitro]

Project description:Tumor Infiltrating Lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the anti-tumor activity of T cell therapies, large-scale in vitro and in vivo CRISPR/Cas9 screens were performed, with the suppressor of cytokine signaling 1 (SOCS1) gene identified as a top T cell-enhancing target. In murine CD8 T cell therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of T central memory cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cell (Texprog) cells in tumors. A comprehensive CRISPR tiling screen of the SOCS1 coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with a sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo anti-tumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.

2023-07-30 | GSE237694 | GEO

Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens [IVP59_mc38gp100]

2023-07-30 | GSE237691 | GEO

Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens [IVP27_B16Ova]

2023-07-30 | GSE237685 | GEO

Effect of SOCS1 overexpression on AML gene expression in OCI-AML2 cell line

Project description:Effect of SOCS1 overexpression on AML gene expression in OCI-AML2 cell line

| PRJNA1218726 | ENA

Rational design of a SOCS1-edited tumor infiltrating lymphocyte therapy for solid tumors using CRISPR/Cas9 screens [scRNA-seq]

2023-07-30 | GSE237569 | GEO