Abstract
Mutations in NOTCH1 are frequently detected in patients with T-cell acute lymphoblastic leukemia (T-ALL) and in mouse T-ALL models. Treatment of mouse or human T-ALL cell lines in vitro with gamma-secretase inhibitors (GSIs) results in growth arrest and/or apoptosis. These studies suggest GSIs as potential therapeutic agents in the treatment of T-ALL. To determine whether GSIs have antileukemic activity in vivo, we treated near-end-stage Tal1/Ink4a/Arf+/- leukemic mice with vehicle or with a GSI developed by Merck (MRK-003). We found that GSI treatment significantly extended the survival of leukemic mice compared with vehicle-treated mice. Notch1 target gene expression was repressed and increased numbers of apoptotic cells were observed in the GSI-treated mice, demonstrating that Notch1 inhibition in vivo induces apoptosis. T-ALL cell lines also exhibit PI3K/mTOR pathway activation, indicating that rapamycin may also have therapeutic benefit. When GSIs are administered in combination with rapamycin, mTOR kinase activity is ablated and apoptosis induced. Moreover, GSI and rapamycin treatment inhibits human T-ALL growth and extends survival in a mouse xenograft model. This work supports the idea of targeting NOTCH1 in T-ALL and suggests that inhibition of the mTOR and NOTCH1 pathways may have added efficacy.
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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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors / physiology
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Proliferation
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Cyclic S-Oxides / pharmacology*
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Cyclin-Dependent Kinase Inhibitor p16 / physiology
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Disease Models, Animal*
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Flow Cytometry
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Humans
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Immunoenzyme Techniques
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Mice
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Mice, Transgenic
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogene Proteins / physiology
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TOR Serine-Threonine Kinases
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Thiadiazoles / pharmacology*
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Tumor Cells, Cultured
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Carrier Proteins
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Cyclic S-Oxides
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Cyclin-Dependent Kinase Inhibitor p16
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MRK 003
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Proto-Oncogene Proteins
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Receptor, Notch1
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Tal1 protein, mouse
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Thiadiazoles
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Amyloid Precursor Protein Secretases