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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

ABSTRACT: The type I JAK inhibitor ruxolitinib is approved for therapy of MPN patients but evokes resistance with longer exposure. Several novel type I JAK inhibitors were studied and we show that they uniformly induce resistance via a shared mechanism of JAK family heterodimer formation.Here we studied the expression profiles of SET2 cell lines persistent to several different type I JAK inhibitors in comparison to naive SET2 cells or in comparison to SET2 cells with acute exposure to ruxolitinib. Analysis of RNA isolated from several type I JAK inhibitor SET2 cell lines in comparison to naïve SET2 cells

ORGANISM(S): Homo sapiens

SUBMITTER: Jeffrey Zhao

PROVIDER: E-GEOD-69827 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differential expression profiles of type I JAK inhibitor persistent vs. naïve MPN cells

Project description:The type I JAK inhibitor ruxolitinib is approved for therapy of MPN patients but evokes resistance with longer exposure. Several novel type I JAK inhibitors were studied and we show that they uniformly induce resistance via a shared mechanism of JAK family heterodimer formation.Here we studied the expression profiles of SET2 cell lines persistent to several different type I JAK inhibitors in comparison to naive SET2 cells or in comparison to SET2 cells with acute exposure to ruxolitinib.

2015-07-11 | GSE69827 | GEO

RNA-seq of human leukemia cell lines, MHH-CALL-4 and MUTZ-5, treated either with Ruxolitinib, FX1, or their combination.

Project description:CRLF2-rearranged acute lymphoblastic leukemia (ALL) is associated with poor clinical outcomes. Although JAK1/2 is activated in this type of ALL, treatment with JAK1/2 inhibitors is insufficient in inhibiting cell growth and inducing apoptosis. BCL6 upregulation upon JAK inhibition may account for this insufficiency. Therefore, we compared gene expression changes of two CRLF2-rearranged ALL cell lines, MHH-CALL-4 and MUTZ-5, treated with either ruxolitinib(a JAK1/2 inhibitor), FX1(a BCL6 inhibitor), their combination, or control.

2022-07-31 | E-MTAB-10755 | biostudies-arrayexpress

set2 buratowski lab

Project description:H3K36 methylation by Set2 targets Rpd3S histone deacetylase to 3Ã¢ÂÂ transcribed regions, repressing internal cryptic promoters and slowing elongation. To further explore the function of this pathway, global transcription was analyzed in yeast experiencing a series of carbon source shifts. Many previously unreported cryptic ncRNAs are induced by specific carbon sources, showing that cryptic promoters can be environmentally regulated. Also, approximately 230 mRNA genes show altered induction or repression upon SET2 deletion. A majority of Set2-repressed genes have overlapping lncRNA transcription. At these promoters, H3K36me3 and deacetylation by Rpd3S leads to slower or reduced induction. Unexpectedly, Set2 derepresses 159 genes, apparently by mediating a balance between Rpd3S and Rpd3L. Therefore, in addition to repression of cryptic transcription, H3K36 methylation maintains optimal expression dynamics of many mRNAs.

2016-09-25 | E-MTAB-4268 | biostudies-arrayexpress

White-to-brown metabolic conversion of human adipocytes by JAK inhibition

Project description:The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of novel therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus Kinase (JAK) activity with no precedent in adipose tissue biology that permanently confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a novel role for the JAK/STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity. Human pluripotent stem-cell derived mesenchymal progenitor cells (PSC-MPCs), white adipose cells (PSC-WA), and brown adipose cells (PSC-BA) were treated with DMSO (as control), a JAK3-inhibitor compound, and a SYK-inhibitor compound respectively. Transcriptomic expression profiling was performed at 24 hours and 7 days respectively. Three biological replicates are available for each condition defined by cell type, compound, and time.

2014-10-31 | E-GEOD-57896 | biostudies-arrayexpress

Effect of the janus kinase inhibitor ruxolitinib on gene expression of chronic lymphocytic leukemia cells in vivo

Project description:Symptomatic previously untreated chronic lymphocytic leukemia patients were treated with the janus kinase (JAK)-inhibitor ruxolitinib (clinicaltrials.gov, number NCT02015208). CLL cells from 6 of the patients were purified prior to commencing ruxolitinib and again 4 or 8 weeks after treatment and analyzed by RNAseq. Ruxolitinib induced a stereotyped response in all patients consisting of a rapid decrease in palpable lymphadenopathy accompanied by increased lymphocytosis and blood lactate dehydrogenase. This response was associated with evidence of inhibited JAK-signaling in CLL cells but activation of other oncogenic pathways.

2022-03-05 | GSE197811 | GEO

JAK/STAT blockade in cHL

Project description:Here we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor. We use five classical Hodgkin lymphoma cell lines: L428, L1236, L540, KMH2, L591

2021-10-15 | GSE185818 | GEO

Inhibition of Jak2 in SET2 cell line with INC424 (two time points and 3 dose levels in triplicate)

Project description:SET2 cells were incubated with increasing concentration of INC424/Ruxolitinib for 3-6 h and RNA was purified. Affymetrix Genechip miRNA array 2.0 was used to identify miRNA species showing a differential expression in treated cells compared with control cells. Exponentially growing SET2 cells were cultured in medium supplemented with 10% fetal bovine serum in the presence or the absence (control cells) of 160, 800 e 1,600 nM concentrations of the JAK1 and JAK2 inhibitor INC424/Ruxolitinib for 3 and 6 h. Triplicate cultures were prepared for each drug concentration and culture time. Total cellular RNA, including small RNAs, was extracted using RNeasy Micro kit (Qiagen, Valencia, CA). Disposable RNA chips (Agilent RNA 6000 Nano LabChip kit, Agilent Technologies, Waldbrunn, Germany) were used to determine the purity/integrity of RNA samples using Agilent 2100 Bioanalyzer. NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies, Wilmington, DE) was used to evaluate the RNA sample concentration, and 260/280 and 260/230 nm ratios were considered to verify the purity of total RNA. Total RNA (500ng for samples) was labeled using the FlashTag Biotin HSR kit (Genisphere) and hybridized to the Affymetrix Genechip miRNA array 2.0 using manufacturer's protocols.

2012-02-08 | E-GEOD-33809 | biostudies-arrayexpress

Human norovirus efficiently replicates in differentiated 3D-human intestinal enteroids

Project description:To investigate the effect of human norovirus infection on the trascriptome of intestinal enteroids in the presence of a Jak kinase inhibitor, Ruxolitinib

2022-10-17 | GSE205007 | GEO

JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Project description:Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the pro-tumorigenic factor cyclooxygenase-2 (COX-2) and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a novel mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

2019-05-16 | GSE131300 | GEO

Innate lymphoid cell development requires TOX-dependent generation of a common ILC progenitor

Project description:Subtypes of innate lymphoid cells (ILC), defined by effector function and transcription factor expression, have recently been identified. In the adult, ILC derive from common lymphoid progenitors in bone marrow, although transcriptional regulation of the developmental pathways involved remains poorly defined. TOX is required for development of lymphoid tissue inducer cells, a type of ILC3 required for lymph node organogenesis, and NK cells, a type of ILC1. We show here that production of multiple ILC lineages requires TOX, as a result of TOX-dependent development of common ILC progenitors. Comparative transcriptome analysis demonstrated failure to induce various aspects of the ILC gene program in the absence of TOX, implicating this nuclear factor as a key early determinant of ILC lineage specification. TOX KO vs. wild tyype

2015-04-27 | E-GEOD-65850 | biostudies-arrayexpress

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