Abstract
NOTCH signaling is important for development and tissue homeostasis and is activated in many human cancers. We investigated a role for NOTCH1 signaling in Sézary syndrome (SS), a cutaneous T-cell lymphoma in which CD4+ tumor cells (Sézary cells) are present in the skin, lymph nodes, and peripheral blood. We show consistent expression of activated NOTCH1 by Sézary cells isolated from peripheral blood of SS patients, as well as the SS-derived cell lines SeAx and HuT78. In addition, immunohistochemical stainings of skin biopsies from SS patients showed consistent expression of nuclear NOTCH1 and its downstream target hairy/enhancer of split-1 (HES1) by Sézary cells. We demonstrate that this persistent NOTCH1 activation is not caused by mutations in the coding regions of NOTCH1 and F-box and WD40 domain protein 7 (FBWX7) genes. Inhibition of NOTCH1 signaling by gamma secretase inhibitors decreased cellular viability and induced apoptosis of Sézary cells. These observations argue that NOTCH1 signaling is functionally involved in the pathogenesis of SS, and inhibition of NOTCH1 signaling represents a new therapeutic target for the treatment of SS.
Publication types
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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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Apoptosis / drug effects
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Apoptosis / physiology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Benzodiazepinones / pharmacology
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Cell Cycle Proteins / genetics
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology
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F-Box Proteins / genetics
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F-Box-WD Repeat-Containing Protein 7
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Female
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Male
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Middle Aged
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Mutation / genetics
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Oligopeptides / pharmacology
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PTEN Phosphohydrolase / genetics
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Protein Structure, Tertiary
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Receptor, Notch1 / chemistry
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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STAT3 Transcription Factor / metabolism
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Sezary Syndrome / drug therapy
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Sezary Syndrome / genetics
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Sezary Syndrome / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism*
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Transcription Factor HES-1
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Ubiquitin-Protein Ligases / genetics
Substances
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2-(2-(3,5-difluorophenyl)-acetylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propionamide
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Basic Helix-Loop-Helix Transcription Factors
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Benzodiazepinones
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Cell Cycle Proteins
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Enzyme Inhibitors
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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Homeodomain Proteins
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NOTCH1 protein, human
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Oligopeptides
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Receptor, Notch1
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STAT3 Transcription Factor
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STAT3 protein, human
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Transcription Factor HES-1
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benzyloxycarbonyl-leucyl-leucyl-norleucinal
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HES1 protein, human
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Ubiquitin-Protein Ligases
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PTEN Phosphohydrolase
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PTEN protein, human
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Amyloid Precursor Protein Secretases