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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. We performed microarray gene expression analysis of GSI treatment in isogenic Pten KO or WT NOTCH1 induced leukemias

ORGANISM(S): Mus musculus

SUBMITTER: Alberto Ambesi-Impiombato

PROVIDER: E-GEOD-71087 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

Project description:To explore the mechanisms downstream of NOTCH1 and PTEN in the control of leukemia cell growth, we performed expression profiling on NOTCH1 induced and Pten-positive T-ALL tumor cells infected with constitutively active AKT (myristoylated-AKT). Constitutive activation of AKT rescues the transcriptional programs induced by NOTCH1 inhibition in Pten-positive T-ALL cells We performed microarray gene expression analysis of GSI treatment in Pten WT NOTCH1 induced leukemias infected with constitutively active AKT (myristoylated-AKT) or empty vector.

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

Expression data from isogenic Pten WT or KO mouse T-ALLs

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-31 | E-GEOD-71090 | biostudies-arrayexpress

MicroRNA expression profiling of mouse NOTCH1-induced tumors following in vivo treatment with gamma-secretase inhibitor

Project description:NOTCH1 is a transcription factor involved in T-cell development and mutations that occur in NOTCH1 gene affects more than 60% of patients affected by T-cell acute lymphoblastic leukemia (T-ALL). In order to identify microRNAs regulated following NOTCH1 inhibition in T-ALL, murine NOTCH1-induced T-cell leukemia were treated with a NOTCH1 inhibitor (DBZ, Dibenzazepine). Tumors were established in irradiated C57BL/6 mice injected with lineage negative progenitors cells transduced with a mutated NOTCH1 allele (HD-ΔPEST NOTCH1). Mice were treated three times, 8 hours apart, with vehicle only (DMSO) or DBZ (5mg/Kg). Total RNA was extracted from tumor samples (spleens of sick mice) and hybridized on Agilent mouse miRNA 8x60K arrays (release 19.0). Each sample was derived from a different mouse (n=3 mice/group). Raw microarray data, preprocessed data matrix and results of differential expression analysis are available together with the applied protocols.

2020-07-30 | E-MTAB-9278 | biostudies-arrayexpress

Gene expression profiling of mouse NOTCH1-induced tumors following in vivo treatment with gamma-secretase Inhibitor

Project description:NOTCH1 is a transcription factor involved in T-cell development and mutations that occur in NOTCH1 gene affects more than 60% of patients affected by T-cell acute lymphoblastic leukemia (T-ALL). In order to identify genes and pathways regulated following NOTCH1 inhibition in T-ALL, murine NOTCH1-induced T-cell leukemia were treated with a NOTCH1 inhibitor (DBZ, Dibenzazepine). Tumors were established in irradiated C57BL/6 mice injected with lineage negative progenitors cells transduced with a mutated NOTCH1 allele (HD-ΔPEST NOTCH1). Mice were treated three times, 8 hours apart, with vehicle only (DMSO) or DBZ (5mg/Kg). Total RNA was extracted from tumor samples (spleens of sick mice) and hybridized on Agilent SurePrint G3 Mouse GE 8x60K arrays. Each sample was derived from a different mouse (n=3 mice/group). Raw microarray data and results of differential expression analysis are available together with the applied protocols.

2020-07-30 | E-MTAB-9279 | biostudies-arrayexpress

Complete hematologic response of early-T-cell progenitor acute lymphoblastic leukemia to the gamma-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case

Project description:Notch pathway antagonists such as gamma-secretase inhibitors (GSI) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early-T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient’s ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-Seq documented that GSI downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSI was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T cell type. H3K27ac superenhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited. RNAseq and H3K27Ac ChIP seq of primary leukemic blasts treated in vitro with vehicle control or gamma-secretase inhibitor BMS-096024

2015-07-29 | E-GEOD-71414 | biostudies-arrayexpress

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.

2009-04-10 | E-GEOD-11184 | biostudies-arrayexpress

Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias

Project description:To formally address the biological activity of Hes1 in vivo, we tested the interaction between oncogenic NOTCH1 and acute Hes1 loss in a retroviral-transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Hes1 wild type and Hes1-/- NOTCH1 induced leukemias

2015-05-07 | E-GEOD-65863 | biostudies-arrayexpress

Transcription profiling of mouse lymphoblasts from animals treated with vehicle or SAHM1

Project description:NOTCH proteins regulate signaling pathways involved in cellular differentiation, proliferation and death. Overactive Notch signaling as been observed in numerous cancers and has been extensively studied in the context of T-cell acute lymphoblastic leukemia (T-ALL) where more than 50% of pateints harbour mutant NOTCH1. Small molecule modulators of these proteins would be important for understanding the role of NOTCH proteins in malignant and normal biological processes. We were interested to measure the global gene expression changes in leukemic cells isolated from mice harbouring a NOTCH1-driven genetically engineered T-cell leukemia after treatment with SAHM1, a synthetically stabilized Î±-helical peptide derived from the MAML1 co-activator protein. Experiment Overall Design: A genetically engineered murine model of NOTCH1-driven T-ALL was developed by retroviral transduction of murine bone marrow with a mutant NOTCH1 allele commonly observed in human T-ALL patients. Transplantation of transduced cells gave rise to T-ALL that was quantifiable by bio-luminescence in our model. After established leukemia was evident by continually increased tumor burden (luminescence) mice were either treated with vehicle alone (5% DMSO in Hank's buffered saline solution) or SAHM1 (30 mg/kg, twice daily, intraperitoneal injection). After five days of treatment, mice receiving SAHM1 had a significant decrease in tumor growth. To measure a pharmacodynamic effect on Notch signaling, circulating lymphoblasts were collected from vehicle- (n=3) and SAHM1-treated (n=3) mice and gene expression profiles were generated.

2009-11-28 | E-GEOD-18351 | biostudies-arrayexpress

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.

2015-08-31 | GSE71087 | GEO

Transcription profiling of human gamma-secretase inhibitor-sensitive and -resistant T-ALL cell lines

Project description:Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates PTEN expression and the activity of the PI3K-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with increased glycolysis and resistance to NOTCH1 inhibition in human T-ALL. These findings identify the transcriptional regulation of PTEN and the control of cellular metabolism as key elements of the oncogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL. Experiment Overall Design: Samples for microarray analysis were prepared and hybridized in Affymetrix Human U133 Plus 2.0 arrays according to the manufacturerâs instructions and as previously described. RNA was extracted from duplicate cultures of GSI-sensitive (ALL-SIL, CUTLL1, DND41, HPB-ALL, KOPTK1) and GSI-resistant (CCRF-CEM, MOLT3, P12 ICHIKAWA, PF382 and RPMI8402) T-ALL cell lines treated for 24 h with vehicle (DMSO) or 500 nM CompE. Interarray intensity differences were normalized with Dchip

2008-06-14 | E-GEOD-5682 | biostudies-arrayexpress

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