Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CRISPR/Cas9 screen of T-ALL cells (DND-41) in the presence of DMSO, CB-103 or GSI (DAPT).

ABSTRACT: The efficacy of targeted therapies for treatment of cancer patients is often limited by development of drug resistance. Potential resistance mechanisms to pharmacological Notch1 inhibition mediated by GSI or CB-103 in T-ALL are currently unclear. Thus, we performed a genome-wide loss-of-function (LoF) CRISPR/Cas9 screen to identify genes responsible for resistance to Notch inhibition and novel combination therapies for efficient treatment of human T-ALL. We used a Notch-dependent human T-ALL cell line, DND-41, which responds moderately to both GSI and CB-103 treatment in vitro. DND-41 cells stably expressing Cas9 were infected with human GeCKO v2 CRIPSR libraries, containing 123,411 sgRNAs targeting 19,050 genes and treated with either vehicle, GSI or CB-103 for 21 days enabling both positive and negative selection of sgRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221576 | GEO | 2023/06/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Pharmacological disruption of the Notch transcription factor complex

Project description:Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance and resistance to cancer therapy. Several strategies, such as monoclonal antibodies (MAbs) against Notch ligands and receptors, as well as small molecule -secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Using a Notch signaling dependent co-culture system, we developed a high-throughput small molecule screening assay. Herein we report the discovery of an orally active small molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T-ALL and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest, thereby impairing proliferation. Notably, CB-103 has the ability to downregulate Notch signaling in GSI-resistant human tumor cell lines that harbor chromosomal translocations and rearrangements in Notch genes. CB-103 mimics Notch loss-of-function phenotypes in flies and mice, retarding tumor growth in xenograft models of breast cancer and patient-derived xenograft models of human leukemia, notably without causing the frequently observed dose-limiting intestinal toxicity induced by other Notch inhibitors. In summary, we describe a pharmacological strategy to interfere with Notch signaling by disrupting the transcriptional regulatory complex it assembles, with therapeutic potential for the treatment of human tumors.

2020-12-19 | GSE148228 | GEO

Gene expression profiles of T-cell acute lymphoblastic leukemia cell lines with and without chronic GSI-treatment

Project description:Here we modeled T-ALL resistance to Notch inhibition, identifying M-bM-^@M-^XpersisterM-bM-^@M-^Y cells that readily expand in the presence of gamma secretase inhibitor (GSI) and the absence of Notch signaling. Rare persister cells are already present in naM-CM-/ve T-ALL populations, and the reversibility of the phenotype is suggestive of an epigenetic mechanism. Relative to GSI-sensitive cells, persisters activate distinct signaling and gene expression programs, and exhibit global chromatin compaction. A shRNA screen identified chromatin regulators whose depletion preferentially impairs persister cell viability, including BRD4, an acetyl-histone reader. BRD4 is up-regulated in the persisters and binds enhancers near genes with critical functions in T-ALL, including MYC and BCL2. Treatment of persisters with the BRD4 inhibitor JQ1 down-regulates these targets and induces growth arrest and apoptosis, at doses well tolerated by GSI-sensitive cells. Prompted by these findings, we examined and established the efficacy of GSI M-bM-^@M-^S JQ1 combination therapy against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia drug resistance and suggest the potential of combination therapies that include epigenetic modulators to prevent and treat resistant disease. Examination of gene expression profiles in the T cell leukemia cell lines DND-41 and KOPT-K1 after chronic treatment with gamma Secretase inhibitor (Compound E, 1 uM, EMD4 Bioscience; persister) or vehicle (naM-CM-/ve). 2 replicates in each group.

2014-03-01 | E-GEOD-54378 | biostudies-arrayexpress

Genome-wide chromatin maps of T-cell acute lymphoblastic leukemia (T-ALL) [ChIP-seq]

Project description:Here we modeled T-ALL resistance to Notch inhibition, identifying M-bM-^@M-^XpersisterM-bM-^@M-^Y cells that readily expand in the presence of gamma secretase inhibitor (GSI) and the absence of Notch signaling. Rare persister cells are already present in naM-CM-/ve T-ALL populations, and the reversibility of the phenotype is suggestive of an epigenetic mechanism. Relative to GSI-sensitive cells, persisters activate distinct signaling and gene expression programs, and exhibit global chromatin compaction. A shRNA screen identified chromatin regulators whose depletion preferentially impairs persister cell viability, including BRD4, an acetyl-histone reader. BRD4 is up-regulated in the persisters and binds enhancers near genes with critical functions in T-ALL, including MYC and BCL2. Treatment of persisters with the BRD4 inhibitor JQ1 down-regulates these targets and induces growth arrest and apoptosis, at doses well tolerated by GSI-sensitive cells. Prompted by these findings, we examined and established the efficacy of GSI M-bM-^@M-^S JQ1 combination therapy against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia drug resistance and suggest the potential of combination therapies that include epigenetic modulators to prevent and treat resistant disease. Examination of 5 different histone modifications and BRD4 in the T cell leukemia cell lines DND-41 and KOPT-K1 after chronic treatment with gamma Secretase inhibitor (Compound E, 1 uM, EMD4 Bioscience; persister) or vehicle (naM-CM-/ve).

2014-03-01 | E-GEOD-54379 | biostudies-arrayexpress

Development of gene expression signatures with lncRNAs for GSI treatment of T-ALL cell lines

Project description:Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting an essential driver role for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from GSI treated T-ALL cell lines, ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publically available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T-cell context. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way towards development of novel therapeutic strategies that target hyperactive Notch1 signaling in human T-cell acute lymphoblastic leukemia. Gene expression was measured in 4 different T-ALL cell lines (HPB-ALL, DND-41, TALL-1 and ALL-SIL) after treatment with GSI or DMSO (solvent control). Cells were collected 12h and 48h after treatment.

2014-10-27 | E-GEOD-61870 | biostudies-arrayexpress

Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

Project description:NOTCH1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to toxicity and development of resistance, thus restricting their clinical efficacy. Here we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta (PKCδ). We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance “in-vitro”. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

2021-03-08 | PXD018744 | Pride

Differential genome-wide profile of histone modifications upon treatment with gamma-secretase inibithor (GSI) DAPT [ChIP-seq]

Project description:The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. Here, we investigated the differential chromatin accessibility, genome-wide distribution of the transcription factor RBPJ and the differential regulation of H3K4me1 and H3K4me3 upon pharmacological inhibition of the Notch pathway with gamma-secretase inibibitor (GSI) DAPT in mouse pre-T (Beko) cells.

2024-03-24 | GSE254806 | GEO

Differential genome-wide profile of RBPJ, H3K4me1 and H3K4me3 as well as differential chromatin accessibility upon treatment with gamma-secretase inibithor (GSI) DAPT (ChIP-Seq).

2024-03-24 | GSE235981 | GEO

Differential genome-wide profile of RBPJ, H3K4me1 and H3K4me3 as well as differential chromatin accessibility upon treatment with gamma-secretase inibithor (GSI) DAPT (ATAC-Seq).

2024-03-24 | GSE235977 | GEO

TooManyPeaks identifies drug-resistant-specific regulatory elements from single-cell leukemic epigenomes [ChIP-seq]

Project description:Purpose: To investigate the impact of GSI resistance on epigenome of Notch-mutated T-ALL Methods: We generated scATAC-seq and H3K27ac ChIP-seq in parental and GSI-resistant cells Results: Using TooManyPeaks, a novel algorithm for scATAC-seq analysis, we identified subpopulation of epigenetically resistant-like parental cell.

2023-08-07 | GSE171098 | GEO

H3K27ac Hi-ChIP analysis in MOLT-4 and DND-41 cells.

Project description:H3K27ac Hi-ChIP analysis was performed in MOLT-4 and DND-41 cells to analyze active chromatin-chromatin interactions after DMSO or ACBI-1 treatment.

2024-07-02 | GSE230591 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data