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Expression data from isogenic Pten WT or KO mouse T-ALLs treated with DBZ or DMSO

ABSTRACT: To investigate the underlying mechanisms mediating resistance to NOTCH inhibition in Pten-null T-ALL tumor cells we performed gene expression profiling of isogenic Pten-positive and Pten-deleted leukemia lymphoblasts after acute treatment with DBZ in vivo. This analysis revealed that, while direct NOTCH1 target genes (such as Hes1, Dtx1, PtcrA, HeyL and Notch3) are effectively downregulated in both Pten-positive and Pten-deleted tumors, genetic ablation of Pten elicits a global reversal of much of the transcriptional effects of NOTCH inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE71087 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA290332

REPOSITORIES: GEO

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Expression data from isogenic Pten WT or KO mouse T-ALLs treated with DBZ or DMSO

Project description:To investigate the underlying mechanisms mediating resistance to NOTCH inhibition in Pten-null T-ALL tumor cells we performed gene expression profiling of isogenic Pten-positive and Pten-deleted leukemia lymphoblasts after acute treatment with DBZ in vivo. This analysis revealed that, while direct NOTCH1 target genes (such as Hes1, Dtx1, PtcrA, HeyL and Notch3) are effectively downregulated in both Pten-positive and Pten-deleted tumors, genetic ablation of Pten elicits a global reversal of much of the transcriptional effects of NOTCH inhibition. We performed microarray gene expression analysis of GSI treatment in isogenic Pten KO or WT NOTCH1 induced leukemias

2015-08-31 | E-GEOD-71087 | biostudies-arrayexpress

Expression data from isogenic Pten WT mouse T-ALLs infected with MSCV Myr-AKT-IRES-mCherry or empty vector, treated with DBZ or DMSO

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Expression data from isogenic Pten WT mouse T-ALLs infected with MSCV Myr-AKT-IRES-mCherry or empty vector, treated with DBZ or DMSO

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2015-08-31 | E-GEOD-71089 | biostudies-arrayexpress

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Transcription profiling of mouse small intestine following treatment with dexamethosone and DBZ

Project description:Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. Experiment Overall Design: Experiments analyzing the interacition of dexamethasone and the gamma-secretase inhibitor DBZ were carried out in 6-week-old C57/Black6 female mice (Jackson Laboratory). In these studies we treated mice with vehicle (DMSO) (n=2), dexamethasone (15 mg/kg) (n=2), DBZ (10 micromol/kg) (n=2) and dexamethasone (15 mg/kg) plus DBZ (10 micromol/kg) (n=2) daily by intraperitoneal injection for 5 days. At the end of the treatment, animals were euthanized and segments of the small intestine were collected and processed for RNA extraction, histological and immunohistochemical analysis.

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Expression data from U373 cells expressing EGFP, MAML1-dn and DTX1-myc

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2012-06-01 | GSE22772 | GEO

Expression data from U373 cells expressing EGFP, MAML1-dn and DTX1-myc

Project description:Glioblastoma multiforme (GBM) is the most malignant and most common tumor of the central nervous system characterized by rapid growth and extensive tissue infiltration. GBM results in more years of life lost than any other cancer type. Notch signaling has been implicated in GBM pathogenesis through several modes of action. Inhibition of Notch leads to a reduction of cancer-initiating cells in gliomas and reduces proliferation and migration. Deltex1 (DTX1) is part of an alternative Notch signaling pathway distinct from the canonical MAML1/RBPJŒ∫-mediated cascade. In this study, we show that DTX1 activates both the RTK/PI3K/PKB as well as the MAPK/ERK pathway. Moreover, we found the anti-apoptotic factor Mcl-1 to be induced by DTX1. In accordance with this, the clonogenic potential and proliferation rates of glioma cell lines correlated with DTX1 levels. DTX1 knock down mitigated the tumorigenic potential in vivo, and overexpression of DTX1 increased cell migration and invasion of tumor cells accompanied by an elevation of the pro-migratory factors PKBŒ≤ and Snail1. Microarray gene expression analysis identified a DTX1-specific transcriptional program - including microRNA-21 - which is distinct from the canonical Notch signaling. We propose the alternative Notch pathway via DTX1 as oncogenic factor in malignant glioma and found low DTX1 expression levels to correlate with prolonged survival of GBM and early breast cancer patients in open source databases. We generated human glioma U373 cell lines stably expressing Enhanced Green Fluorescent Protein (EGFP), human Deltex1-Myc Tag (DTX1-myc), or Master Mind Like 1 - dominant negative (MAML1-dn) to compare differences in overall gene expression. We included 3x EGFP control samples, 3x DTX1-myc, and 3 MAML1-dn samples.

2012-05-31 | E-GEOD-22772 | biostudies-arrayexpress

RNAseq in Pten enhancer wild-type or deleted mouse T-ALLs

Project description:RNAseq in Pten enhancer wild-type or deleted mouse T-ALLs

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Single cell changes in DBZ or DMSO treated cells derived from Apc-mutant organoid cultures

Project description:We made intestinal organoid cultures from Villin-CreERT2;Apcflox/flox mice. Organoids were subjected to 4-OH-Tam treatment, whereafter Apc mutant organoids were selected in R-Spondin free medium. DBZ or DMSO treatment was started on day 3. On day 8, organoids were dissociated to obtain single cells and analyzed using the Chromium Single-cell 3'RNA-sequencing system

2018-08-21 | GSE118055 | GEO

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [scRNA-Seq]

Project description:Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we utilized an in vitro air-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of control vs NICD3 -transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/β-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+ cells primarily clustered with SCGB1A1+ and NOTCH3+ cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI cultures in vitro and in the human and mouse airway epithelium in vivo. siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+ club cells, along with a corresponding increase in KRT8+ BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.

2021-03-04 | GSE168127 | GEO

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