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Gene expression profile of the human T-ALL cell line JURKAT after TYK2 and STAT1 knockdown

ABSTRACT: Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK kinase activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of IL-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the anti-apoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44652 | GEO | 2013/03/18

SECONDARY ACCESSION(S): PRJNA190703

REPOSITORIES: GEO

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Gene expression profile of the human T-ALL cell line JURKAT after TYK2 and STAT1 knockdown

Project description:Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK kinase activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of IL-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the anti-apoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. Human T-ALL cell line JURKAT cells were transduced with TYK2 (TYK2#2 or #3), STAT1 (STAT1#2 or #3) or control shRNAs (GFP and Luc). Experiment was done in biological duplicate ("dup1" and "dup2") . A total of 12 RNA samples (4 control, 4 TYK2 knockdown and 4 STAT1 knockdown) were used for microarray gene expression analysis.

2013-03-18 | E-GEOD-44652 | biostudies-arrayexpress

Comparison of the expression profiles of wild-type (WT), Tyk2-deficient (Tyk2-/-) and kinase-inactive Tyk2 mutant (Tyk2K923E) NK cells

Project description:Define the impact of Tyk2 and Tyk2K923E on the transcriptome of NK cells Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2-/- ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2-/- mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2-/- and Tyk2K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2-/- NK cells (and to a lesser extent of Tyk2K923E NK cells) is impaired. In contrast, the production of interferon ? (IFN?) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2K923E NK cells against a range of target cells in vitro is higher than that of Tyk2-/- NK cells. Consistently, Tyk2K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2’s kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy. Splenic NK cells derived from WT, Tyk2-/- and Tyk2K923E mice (DX5-MACS enriched from 3-4 mice per genotype) were grown in the presence rhIL-2 (5000 U/ml) for 7 days. Three independent expreiments (= biological replicates)

2015-04-28 | E-GEOD-68294 | biostudies-arrayexpress

Comparison of the expression profiles of wild-type (WT), Tyk2-deficient (Tyk2-/-) and kinase-inactive Tyk2 mutant (Tyk2K923E) NK cells

Project description:Define the impact of Tyk2 and Tyk2K923E on the transcriptome of NK cells Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2-/- ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2-/- mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2-/- and Tyk2K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2-/- NK cells (and to a lesser extent of Tyk2K923E NK cells) is impaired. In contrast, the production of interferon γ (IFNγ) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2K923E NK cells against a range of target cells in vitro is higher than that of Tyk2-/- NK cells. Consistently, Tyk2K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2’s kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

2015-04-28 | GSE68294 | GEO

Analysis of RNA synthesis in MCMV infected Wild type and Tyk2-/- bone marrow-derived macrophages 2 macrophage interferon antiviral cascade

Project description:Murine Cytomegalovirus infection of macrophages results in hundreds of alterations in cellular gene expression. Many of these alterations are due to the autocrine and paracrine effects of virus-elicited type I interferons released by infected cells. Key to the function of type I interferons is the JAK-STAT signalling pathway. The extracellular binding of Type I IFN to the type 1 interferon receptor (consisting of IFNAR1 and IFNAR2) results in cytoplasmic activation of Tyrosine Kinase 2 (TYK2) and Janus Kinase 1 (JAK1) and the subsequent phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 and 2 bind IRF9 forming a complex known as ISGF3. ISGF3 is translocated to the nucleus where it directly interacts with Interferon-sensitive regulatory elements in the genomic DNA. This binding results in direct and indirect alterations in the transcription of hundreds of genes. Whilst the functions of Tyk2 and changes in transcript abundance following MCMV infection are well characterised, little is known about changes in RNA synthesis at very early times after infection in intact cells or cells with a defective IFN signalling pathway. Microarrays were used to analyse alterations in transcript synthesis 30 to 60 mins and 360 to 390 minutes after MCMV infection of Wild Type or Tyk2-/- BMDM.

2019-02-22 | GSE126867 | GEO

TYK2 regulates human pancreatic beta-cell development and its responses to interferon-alpha [ultradeep]

Project description:Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic b-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-I interferon (IFN) mediated intracellular signalling. To study the role of TYK2 in human pancreatic b-cell development and response to IFNa, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Unexpectedly, loss of TYK2 compromised the emergence of endocrine precursors by regulating KRAS expression, however, mature b-cell function was not affected. In the mature stem cell-derived islets, the loss or inhibition of TYK2 prevented IFNa-induced antigen processing and presentation, including MHC Class I expression, enhancing their survival against T-cell cytotoxicity. These results identify an unsuspected role for TYK2 on b-cell development and support TYK2 inhibition in adult b-cells as a potent therapeutic target to halt T1D progression.

2022-09-19 | GSE190727 | GEO

TYK2 regulates human pancreatic beta-cell development and its responses to interferon-alpha [tyk2_bulkseq]

2022-09-19 | GSE190725 | GEO

TYK2 regulates human pancreatic beta-cell development and its responses to interferon-alpha [tyk2_scRNAseq]

2022-09-19 | GSE190726 | GEO

Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity

Project description:STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing Stat1-Y701F. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo suggesting a so-far unknown cytoplasmic function. Using immunofluorescence technology we uncovered the recruitment of STAT1 to the immunological synapse during NK cell killing. A Stat1ind mouse expressing FLAG-tagged STAT1α was used to study the STAT1α interactome in NK cells. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. We propose a novel function for STAT1 in the immunological synapse of NK cells regulating tumor surveillance and cytotoxicity.

2016-10-07 | PXD002206 | Pride

Lack of TYK2 Signaling Enhances Host Resistance to Candida albicans Skin Infection

Project description:Candida albicans is the most common human fungal pathogen, causing diseases ranging from local to life-threating systemic infections. Tyrosine kinase 2 (TYK2), a crucial mediator in several cytokine signaling pathways, has been associated with protective functions in various microbial infections. However, its specific contribution in the immune response to fungal infections has remained elusive. In this study, we show that mice lacking TYK2 or its enzymatic activity exhibit enhanced resistance to C. albicans skin infections, limiting fungal spread and accelerating wound healing. Impaired TYK2-signaling prompted the formation of a distinctive layer of necrotic neutrophils around the fungal pathogens. Transcriptomic analysis revealed TYK2's pivotal role in regulating interferon-inducible genes in neutrophils, thereby impacting their antifungal capacity during infection. Furthermore, we show that TYK2-dependent interferon-gamma (IFNg) production contributes to fungal dissemination from the skin to the kidneys. Our study uncovers a hitherto unrecognized detrimental role of TYK2 in cutaneous C. albicans infections.

2024-10-14 | GSE278915 | GEO

hCAF1/CNOT7 regulates interferon signaling by targeting STAT1

Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).

2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress

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