Gene expression of Kit225 cells upon NC1153 treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17007 | GEO | 2010/07/08
SECONDARY ACCESSION(S): PRJNA117747
REPOSITORIES: GEO
Similar Datasets
Project description:NC1153 was shown to inhibit JAK3 tyrosine kinase. Lymphocytes survival depends on the integrity of STAT5, the primary downstream target of JAK3. In this study microarrays were used to test the effect of a JAK3 inhibitor, NC1153, on the gene expression profile of a human leukemia cell line. Kit225 human leukemia cells were treated with NC1153 or DMSO (vehicle) for 12 h then harvested for RNA isolation.
2010-07-08 | E-GEOD-17007 | biostudies-arrayexpress
Project description:Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occuring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared to JAK3 or HOXA9 alone. Integrated RNA-seq, ChIP-seq and ATAC-seq revealed that STAT5 and HOXA9 have co-occupancy across the genome resulting in enhanced STAT5 transcriptional activity and ectopic activation of Fos/Jun (AP-1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9 expressing cells.
2018-01-26 | GSE109653 | GEO
Project description:The transcription factors STAT5A and STAT5B are essential downstream mediators of many tyrosine kinases, particularly in hematopoietic cancers. As such, STAT5 is activated by FLT3-ITD, which is a constitutively active tyrosine kinase driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 function is of significant clinical value. Here, we describe the novel small molecular weight inhibitor AC-4-130 that directly binds to the phosphotyrosine (pY)-binding pocket of the STAT5 SH2 domain, thereby disrupting STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent induction of gene transcription. AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Importantly, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. In summary, we report the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor that can efficiently block pathological levels of STAT5 activity in AML. The synergistic effects of AC-4-130 tyrosine kinase inhibitors as well as emerging treatment strategies provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.
2018-09-03 | GSE103510 | GEO
Project description:In this study we compared the effects of IL-2, IL-15, and IL-21 on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from the CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 that signal through receptors that share the common gamma chain and the beta chain modulated the expression of >1,000 genes, IL-21 that signals via the receptor also containing gamma chain up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3. However, only IL-2 and IL-15 strongly activated STAT5, PI3K/Akt, and MEK/ERK signaling pathways. In contrast, IL-21 selectively activated STAT3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3- and Jak1-kinase dependent. These findings document the vastly different impact of IL-2 and IL-15 vs. IL-21 on malignant CD4+ T cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, NK, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. Experiment Overall Design: Sez-4 cell line was starved of IL-2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2h followed by pre-treating for 30â?? with pan-Jak inhibitor (300 nM), Jak3 inhibitor (300 nM), or drig solvent and cultured with IL-2 (200U) or medium alone for 4 h.
2008-04-09 | E-GEOD-8687 | biostudies-arrayexpress
Project description:T-ALL is characterized by deregulation of transcriptional control and impairment of epigenetic homeostasis. We observed that T-ALL cases with mutations in the IL7R-JAK-STAT pathway frequently harbor inactivating mutations in the PRC2 complex, in particular SUZ12 mutations. PRC2 is an epigenetic complex responsible for writing the H3K27me3 mark associated with gene repression. To assess whether loss of SUZ12 cooperates with mutant JAK3 signaling during T-ALL development, we expressed the JAK3(M511I) mutant in mouse bone marrow cells in vivo and tested the effect of Cas9-mediated inactivation of Suz12 on leukemia development. The mice developed a T-cell leukemia that infiltrated most hematological organs (bone marrow, thymus, spleen, lymph nodes, blood). At time of sacrifice the majority of cells in the blood and hematopoietic organs was JAK3(M511I) positive and Suz12 negative. Reduced Suz12 protein and H3K27me3 levels were confirmed with flow cytometry. Moreover, JAK3(M511I) also cooperates with Suz12 gRNA-mediated inactivation in vitro. Pro-T cells carrying both JAK3(M511I) and Suz12 gRNA were able to transform to IL7 independent growth, whereas single mutant (JAK3(M511I) only or Suz12 gRNA only) pro-T cells could not. In order to get insight in the mechanism of cooperation between JAK3 mutant signaling and Suz12 inactivation, we performed and integrated RNA- and ChIP-sequencing (Suz12, H3K27me3, H3K27Ac, H3K4me1, H3K4me3) on leukemic cells from the mice. This showed a global upregulation of many genes, including known PRC2 target genes upon loss of Suz12. Moreover, Suz12 was bound to promoters of Wnt signaling genes (Fzd7, Lrp4) and Wnt target genes (Axin2, Jag2, Mmp9), concomitant with high H3K27me3 levels. Loss of Suz12 led to drastic reduction of H3K27me3 at these loci and upregulation of these Wnt genes. As Wnt signaling is ectopically activated, we wanted to test whether JAK3(M511I) + Suz12 gRNA cells are more sensitive to Wnt inhibitor. JAK3(M511I) + Suz12 pro-T cells and leukemic spleen cells exhibited increased sensitivity to Wnt inhibitor compared to JAK3 mutant control cells, indicating that Wnt signaling contributes to the cooperation between Suz12 loss and JAK3 mutant signaling. In conclusion, our data show that Suz12 inactivation cooperates with mutant JAK3 signaling to drive leukemia development in vivo and demonstrates the use of Cas9 transgenic mice to study the role of tumor suppressor genes in T-ALL mouse models. Moreover, Suz12 loss leads to ectopic activation of Wnt signaling, a pathway contributing to the cooperation of Suz12 loss and JAK3 mutant signaling that can also be targeted with inhibitors.
2019-03-01 | GSE122496 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T-cell cancer. Hotspot mutations in JAK-STAT pathway members IL7R, JAK1 and JAK3 were analyzed in depth, but the role of STAT5A or STAT5B in T-cell development or T-ALL transformation is unclear. Importantly, the driver mutation STAT5BN642H encodes the most frequent activating STAT5 variant in T-ALL and it correlated with disease relapse upon chemotherapy. Here, we show that STAT5BN642H promotes T-ALL-like cancer in mice and transcriptionally upregulates a collection of genes that are involved in T-cell receptor signaling (TCR), even in the absence of surface TCR. Importantly, these genes were also overexpressed in human T-ALL patients. Moreover, T-ALL cells were sensitive to pharmacologic inhibition of STAT3/5 or ZAP70 activity. Collectively, we discovered how hyperactive STAT5 induces and accelerates T-ALL and we suggest therapeutic targeting using selective ZAP70 or STAT5 activity inhibitors in a subgroup of T-ALL patients with prominent IL-7R-JAK1/3-STAT5 activity.
2024-04-15 | GSE219155 | GEO
Project description:The transcription factor STAT5 plays a critical role in B cell Acute Lymphoblastic Leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NFkB and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NFκB or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL.
2017-04-03 | GSE86878 | GEO
Project description:Mutations in the interleukin-7 receptor (IL7R) or the JAK3 kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here, we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells and human JAK3 mutated T-ALL samples. Novel peptides shown to be downstream of mutant JAK3 regulating RNA metabolism as well as epigenetic and apoptotic processes were validated using targeted PRM proteomics.
2017-07-14 | MSV000081327 | MassIVE
Project description:In this study we compared the effects of IL-2, IL-15, and IL-21 on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from the CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 that signal through receptors that share the common gamma chain and the beta chain modulated the expression of >1,000 genes, IL-21 that signals via the receptor also containing gamma chain up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3. However, only IL-2 and IL-15 strongly activated STAT5, PI3K/Akt, and MEK/ERK signaling pathways. In contrast, IL-21 selectively activated STAT3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3- and Jak1-kinase dependent. These findings document the vastly different impact of IL-2 and IL-15 vs. IL-21 on malignant CD4+ T cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, NK, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. Experiment Overall Design: Sez-4 cell line was starved of IL2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2 h followed by addition of IL-2 (200U), IL-15 (20ng/mL), or IL-21 (100 ng/ml) or medium alone for 4 h.
2008-04-09 | E-GEOD-8685 | biostudies-arrayexpress
Project description:The transcription factor STAT5 plays a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components encoded by Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NF-κB and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NF-κB or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL.
2016-11-30 | GSE25643 | GEO