Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia

ABSTRACT: Gamma Secretase Inhibitors (GSIs) effectively block the activation of oncogenic protein Notch homolog-1 (NOTCH1), a frequent event in T-cell Acute Lymphoblastic Leukemia (T-ALL). However, their clinical application is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling and subsequent increase in goblet cell differentiation in the gut. Genome-wide CRISPR loss-of-function (LOF) screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, genetic deletion or pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924 rescued GSI-induced differentiation and cell death in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1 (HES1), a known NOTCH1 target and a regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in murine Notch1-induced model of T-ALL showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. To elucidate the mechanisms mediating LS174T (adenocarcinoma cell line) differentiation upon NOTCH inhibition, we performed gene expression profiling in LS174T cells treated with vehicle (DMSO) or GSI (CompE) (250 nm) for 48 hours

ORGANISM(S): Homo sapiens

PROVIDER: GSE245371 | GEO | 2025/04/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia

Project description:Gamma Secretase Inhibitors (GSIs) effectively block the activation of oncogenic protein Notch homolog-1 (NOTCH1), a frequent event in T-cell Acute Lymphoblastic Leukemia (T-ALL). However, their clinical application is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling and subsequent increase in goblet cell differentiation in the gut. Genome-wide CRISPR loss-of-function (LOF) screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, genetic deletion or pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924 rescued GSI-induced differentiation and cell death in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1 (HES1), a known NOTCH1 target and a regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in murine Notch1-induced model of T-ALL showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. We used microarray to profile the gene expression in mouse intestinal stem cells upon NOTCH1 inhibition through GSI (DBZ treatment). This will allow us to explore the mechanisms of NOTCH1 inhibition in intestinal cell fate in vivo.

2025-04-01 | GSE245370 | GEO

Human T-ALL cell line response to inhibition of Notch signaling

2011-08-01 | GSE29959 | GEO

Human T-ALL cell line response to inhibition of Notch signaling

Project description:Analysis of five Notch signaling-dependent human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) treated with gamma-secretase inhibitor (GSI) to block Notch signaling. Samples include parental cells, cells rescued by retroviral transduction with ICN (a GSI-independent form of activated Notch1), and cells retrovirally transduced with c-Myc (an important downstream target of Notch1). Results allow segregation of bona fide Notch targets from other genes affected by gamma-secretase inhibition as well as from targets downstream of c-Myc. Thirty samples were analyzed. Five human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) were treated with gamma-secretase inhibitor (1.0 micromolar compound E) vs. DMSO vehicle control for 12 hours. Each cell line was also retrovirally transduced with ICN or c-Myc, FACS sorted, and then treated with GSI vs. DMSO.

2011-07-31 | E-GEOD-29959 | biostudies-arrayexpress

Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumors

Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.

2023-03-20 | GSE216043 | GEO

Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumors II

2023-03-20 | GSE225852 | GEO

Effect of NOTCH-γ-secretase inhibitor LY3039478 therapy on patient derived xenograft (PDX) mouse model of intrahepatic cholangiocarcinoma

Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. Recently, aberrant Notch signaling was reported in iCCA carcinogenesis. Specifically, altered expression and/or activation of the receptors Notch1/2 suggests a role for Notch pathway overactivation during iCCA formation and progression. In this study, we examined the effects of Notch inhibition by γ-secretase inhibitor, LY3039478 in human iCCA cell lines and in an excellent patient derived-xenograft (PDX) model. Expression of several Notch pathway components, including NICD, Hes1, and DLL4, were reduced after GSI treatment. Moreover, LY3039478 inhibits cell migration and invasion while in GSI-treated mice, tumor growth was delayed compared to vehicle and chemotherapy. These results support the notion that Notch inhibition by GSI may reduce in vivo tumorigenesis. In addition, GSI reduces in PDX model VEGFA and MMP13 involved in capillary tube formation and tumor progression. Here, we therefore show a link between the efficacy of Notch inhibition and the tumor microenvironment through LY3039478 that slows tumor progression compared to control mice blocking angiogenesis via MMP13 downregulation. We used microarray technology to understand the molecular mechanisms affected by LY3039478. Cholangiocarcinoma PDX model was employed in this analysis.

2020-07-27 | GSE134114 | GEO

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

Discovery of biomarkers predictive of GSI response in triple negative breast cancer and adenoid cystic carcinoma

Project description:Next generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple negative breast cancers (TNBC, 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with pacitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in TNBC patients. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD low tumors without NOTCH1 mutations were resistant. Gene expression profiling for Notch-sensitive cancer cell lines using RNA-seq, each sample with triplicates

2014-08-14 | E-GEOD-59810 | biostudies-arrayexpress

NOTCH1/RBPJ complexes drive target gene expression through dynamic interactions with super-enhancers

Project description:The main oncogenic driver in T-lymphoblastic leukemia (T-LL) is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase (GSI) inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1 binding sites are insensitive to GSI. Here, we demonstrate that fewer than 10% of NOTCH1 binding sites show dynamic changes in NOTCH1 occupancy when T-LL cells are toggled between the Notch-on and –off states with GSI. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T cell development and in T-LL, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1 binding sites co-occupy chromatin domains defined by constitutive binding of CCCTC binding factor (CTCF), which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in super-enhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of super-enhancers and in the promoters of nearby Notch target genes. These findings link regulation of super-enhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes. NOTCH1/RBPJ complexes binding dynamics in human T-LL

2013-12-27 | E-GEOD-51800 | 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. 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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