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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / enzymology
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Child
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Cohort Studies
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / metabolism
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Oligopeptides / pharmacology*
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Oligopeptides / therapeutic use
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protease Inhibitors / pharmacology*
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Protease Inhibitors / therapeutic use
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Inhibitors*
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RNA, Messenger / metabolism
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RNA, Neoplasm / metabolism
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Receptors, Notch / genetics
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Receptors, Notch / physiology*
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Risk
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Specific Pathogen-Free Organisms
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Transcription, Genetic / drug effects
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Xenograft Model Antitumor Assays
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Young Adult
Substances
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Antineoplastic Agents
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Neoplasm Proteins
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Oligopeptides
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Protease Inhibitors
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Proteasome Inhibitors
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Notch
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benzyloxycarbonyl-leucyl-leucyl-norleucinal
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Amyloid Precursor Protein Secretases
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Proteasome Endopeptidase Complex