Dynamic gene expression in T-ALL following treatment and release of gamma-secretase inhibition [GRO-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE115894 | GEO | 2019/08/04
REPOSITORIES: GEO
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Project description:Dynamic gene expression in T-ALL following treatment and release of gamma-secretase inhibition [GRO-Seq]
| PRJNA476373 | ENA
Project description:Combination of GSI with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells We used microarrays to detail the mechanism of synergy of GSI and fludarabine combination in NOTCH1-mutated CLL cells
2013-09-21 | GSE51044 | GEO
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
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
Project description:Oncogenes NOTCH1 and MYC directly regulate HSF1 and other critical proteins of the stress-response pathway in T-ALL. This GRO-Seq experiment demonstrates that release from NOTCH1 inhibition results in upregulation of HSF1 and other key HSPs.
2018-03-20 | GSE101803 | GEO
Project description:Combination of GSI with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells We used microarrays to detail the mechanism of synergy of GSI and fludarabine combination in NOTCH1-mutated CLL cells Global RNA expression in CLL primary cells treated with GSI, fludarabine and the combination at 48 hours of treatment
2013-09-21 | E-GEOD-51044 | biostudies-arrayexpress
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. Keywords: Drug sensitivity comparison
2007-09-01 | GSE5682 | GEO
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 (GSI), 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. Analysis of gene expression in GSI-responsive and GSI-resistant cell lines treated with Compound E identifies differential resopnses to GSI. Keywords: Drug response
2008-08-20 | GSE5716 | GEO
Project description:The structure and function of the gamma-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the gamma-secretase complex that involves a conformation- and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the gamma-secretase structure and its conformational variability. Under steady-state conditions, the complex adopts three major conformations, which differ in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate-binding sites by inhibitors differentially stabilizes subpopulations of particles with compact conformations, whereas a mutation linked to familial Alzheimer disease results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the csecretase complex as a dynamic population of interconverting conformations, involving rearrangements at the nanometer scale and a high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect amyloid beta (Abeta) generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely to be instrumental for highly allosteric behavior of the enzyme.
| S-EPMC4311135 | biostudies-other
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