ArticleLeukemia2011
GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia.
Article in Leukemia, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- A novel model based on ferroptosis-related lncRNAs for predicting prognosis and adjuvant therapy response in colon adenocarcinoma.Discover oncology · 2026Article
- Pan-cancer multi-omics profiling of gasdermins identifies GSDMD as an immune-related prognostic biomarker in kidney renal clear cell carcinoma.Discover oncology · 2026Article
- Development and validation of an m6A and autophagy related lncRNAs signature for predicting survival and modulating the immune microenvironment in esophageal squamous cell carcinoma.Frontiers in immunology · 2026Article
- FoxO1, together with Notch1, promotes microglial activation to induce pathological changes in the retinal vasculature under hypoxia.Cellular and molecular life sciences : CMLS · 2025Article
- Novel cuproptosis-related lncRNAs risk model to predicting prognosis and guiding immunotherapy for OSCC patients.Discover oncology · 2025Article
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- Prognostic RNA-editing signature predicts immune functions and therapy responses in gliomas.Frontiers in genetics · 2023Article
- A five-cuproptosis-related LncRNA Signature: predicting prognosis, assessing immune function & drug sensitivity in lung squamous cell carcinoma.Journal of Cancer · 2023Article
- Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in primary infection.Journal of leukocyte biology · 2022Article
- Altered pathways and targeted therapy in double hit lymphoma.Journal of hematology & oncology · 2022Review
- Cuproptosis-related lncRNA signatures predict prognosis and immune relevance of kidney renal papillary cell carcinoma.Frontiers in pharmacology · 2022Article
- Transcriptome Signature of Vγ9Vδ2 T Cells Treated With Phosphoantigens and Notch Inhibitor Reveals Interplay Between TCR and Notch Signaling Pathways.Frontiers in immunology · 2021Article
- Article
- The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- Notch/CXCR4 Partnership in Acute Lymphoblastic Leukemia Progression.Journal of immunology research · 2019Review
- Article
- Characterization of a new B-ALL cell line with constitutional defect of the Notch signaling pathway.Oncotarget · 2018Article
- Article
- Combining a GSI and BCL-2 inhibitor to overcome melanoma's resistance to current treatments.Oncotarget · 2016Article
- γ-Secretase inhibitor I inhibits neuroblastoma cells, with NOTCH and the proteasome among its targets.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Gamma secretase inhibitors (GSIs) comprise a growing class of compounds that interfere with the membrane-bound Notch signaling protein and its downstream intra-nuclear transcriptional targets. As GSI-I (Z-LLNle-CHO) is also a derivative of a widely used proteosome inhibitor MG-132, we hypothesized that this compound might be active in precursor-B acute lymphoblastic leukemia (ALL) cell lines and patient samples. We found that GSI-I treatment of precursor-B ALL blasts induced apoptotic cell death within 18-24 h. With confirmation using RNA and protein analyses, GSI-I blocked nuclear accumulation of cleaved Notch1 and Notch2, and inhibited Notch targets Hey2 and Myc. Microarray analyses of 207 children with high-risk precursor-B ALL demonstrate that Notch pathway expression is a common feature of these neoplasms. However, microarray studies also implicated additional transcriptional targets in GSI-I-dependent cell death, including genes in the unfolded protein response, nuclear factor-κB and p53 pathways. Z-LLNle-CHO blocks both γ-secretase and proteosome activity, inducing more robust cell death in precursor-B ALL cells than either proteosome-selective or γ-secretase-selective inhibitors alone. Using Z-LLNle-CHO in a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) precursor-B ALL xenograft model, we found that GSI-I alone delayed or prevented engraftment of B-lymphoblasts in 50% of the animals comprising the experimental group, suggesting that this compound is worthy of additional testing.
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Registered trials
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