Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

T cell lymphoma associated STAT3 variants impose a type 1 regulatory phenotype

ABSTRACT: STAT3 signaling is fundamental to T cells, where it underlies basic cellular processes like metabolism and apoptosis, and specialized processes like differentiation and cytokine production. However, mutations of STAT3 are strikingly prevalent in T cell cancers and aberrant or excessive STAT3 signaling is thought to mobilize cellular pathways that encourage malignancy. To better understand how STAT3 mutations drive T cell cancers, we compared two frequent cancer-associated variants, Y640F and N647I, at cellular and molecular levels. Using a retrogenic system, we demonstrate that they are qualitatively similar yet quantitatively distinct; each bears a gain-of-function phenotype but Y640F has greater transcriptome-wide effects. We also discovered that these and other common STAT3 mutants invoke a T regulatory 1 (Tr1) gene program characterized by expression of IL-10 and other factors that dampen T cell responses, most notably LAG3 and CD39. Importantly, Tr1 ’skewing’ is evident in both mouse T cells expressing cancer-associated STAT3 variants and humans afflicted with T cell malignancies. These studies advance current understanding of how cancer-associated mutations impact STAT3 function and reveal anti-inflammatory properties that may help transformed T cells persist, expand and/or avoid eradication.

ORGANISM(S): Mus musculus

PROVIDER: GSE328028 | GEO | 2026/04/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genome Wide Binding profile and transcriptome of STAT3 and STAT3 Mutant Y640F in STAT3 Wildtype and STAT3 Mutant Y640F hematopoietic progenitor cell lines

Project description:In many human cancers the transcription factor STAT3 is constitutively active and contributes to oncogenesis, tumour growth and progression. Recently, gain-of-function mutations of STAT3 have been identified in patients suffering from various haematopoietic malignancies and are postulated to enhance the transcriptional activity of STAT3. We investigated the gene expression and binding profile of the most common STAT3 mutant Y640F compared to wild-type STAT3, describing it's mechanism of action and pinpointing to novel therapeutic intervention sites.

2023-01-25 | GSE211111 | GEO

Genome Wide Binding profile and transcriptome of STAT3 and STAT3 Mutant Y640F in STAT3 Wildtype and STAT3 Mutant Y640F hematopoietic progenitor cell lines

Project description:Genome Wide Binding profile and transcriptome of STAT3 and STAT3 Mutant Y640F in STAT3 Wildtype and STAT3 Mutant Y640F hematopoietic progenitor cell lines

| PRJNA868941 | ENA

T cell lymphoma associated STAT3 variants impose a type 1 regulatory phenotype

Project description:T cell lymphoma associated STAT3 variants impose a type 1 regulatory phenotype

| PRJNA1453535 | ENA

ZNF341 controls STAT3 expression and thereby immunocompetence

Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

2018-05-02 | GSE107719 | GEO

Genome-wide transcriptome analysis in PBMCs of HIES patient A.II.1 compared to healthy sibling A.II.5

Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

2018-05-04 | GSE109030 | GEO

The gene expression profile of CD4 T-cells with STAT3 gain-of-function and loss-of-function mutations

Project description:Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need. Methods: To decipher the crucial cellular subsets and disease biology associated with STAT3 gain-of-function mutations, we examined the gene expression profile of STAT3 gain-of-function and loss-of-function mutations in unstimulated, IL10- or IL21-stimulated CD4 T cells and compared them to healthy donor cells. Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. We observed strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production. Transcriptome profiling of murine CD4+ and CD8+ T-cells revealed commonly dysregulated genes and a STAT3 gain-of-function signature that was used to discriminate between STAT3 gain-of-function and healthy control patients. Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity

2023-10-06 | GSE198963 | GEO

THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors

Project description:Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signaling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

2016-12-15 | GSE79955 | GEO

ChIP-seq of Stat3 with DNA binding sites mutation in human colon cancer SW480

Project description:STAT3 is determined to play a crucial role in JAK/STAT signaling pathway. The mutations and copy number alteration of STAT3 can cause cancers and other diseases. The 317-567 amino acid domain of STAT3 protein contributes to binding with genomic DNA for gene activation. However, the impact of the mutations within DNA binding domain of STAT3 on the genomic binding pattern is not fully understood. Stat3 was deleted the 400-411 amino acid residue of \\"NNGSLSAEFKHL\\" using CRISPR-CAS9 in human colon cancer cells SW480. The cells were performed STAT3 ChIP-seq to investigate the genome-wide binding pattern of STAT3 between wild type and mutant STAT3 of SW480.

2020-07-06 | E-MTAB-8417 | biostudies-arrayexpress

Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells

Project description:CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases. The transcriptome of human Tr1 cell clones to that of TH0 cell clones either unstimulated or stimulated for 6 and 16 h. Tr1 and TH0 cell clones were isolated from peripheral blood of 2 Healthy Donors (HDs). mRNA from T cell clones unstimulated (t0, n=4 Tr1 cell clones and n=10 TH0 cell clones) or stimulated with immobilized anti-CD3 and soluble anti-CD28 mAbs (6h and 16h, n=4 Tr1 cell clones and n=5 TH0 cell clones) was isolated. Differential expression of 28869 genes was investigated by whole transcript Affymetric chips.

2013-12-20 | E-GEOD-53514 | biostudies-arrayexpress

Gene expression profiles of CAR-T cells expressing constitutively active mutants of STAT3 and STAT5 [STAT3_3+5 _CART_rested]

Project description:Augmenting cytokine signaling represents a pivotal strategy to enhance the therapeutic efficacy of chimeric antigen receptor (CAR) T cell therapy. However, the distinct roles of the downstream transcription factors STAT3 and STAT5 remain insufficiently defined. To elucidate their individual contributions, we engineered CAR-T cells to express constitutively active mutants of STAT3 (Y640F; caSTAT3) or STAT5 (N642H; caSTAT5). In vitro, caSTAT3 CAR-T cells demonstrated superior effector functions and a pronounced memory-associated phenotype, accompanied by broader transcriptomic alterations compared to their caSTAT5 counterparts. Despite impaired proliferative capacity in vitro, caSTAT3 CAR-T cells exhibited reduced systemic toxicity and sustained antitumor activity across multiple in vivo tumor models. In contrast, caSTAT5 CAR-T cells showed efficient intratumoral accumulation but also disseminated into non-malignant tissues, resulting in fatal toxicity. Notably, co-expression of caSTAT3 and caSTAT5 synergistically promoted both effector function and long-term persistence of CAR-T cells. Collectively, these findings provide mechanistic insights into the differential roles of STAT3 and STAT5 signaling in shaping the functional and safety profiles of CAR-T cell therapies.

2026-02-19 | GSE296803 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data