Abstract
Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adolescent
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Alleles
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases
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Cell Cycle
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Cell Line, Tumor
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Child
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Dimerization
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Endopeptidases / metabolism
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Frameshift Mutation
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Humans
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Leukemia-Lymphoma, Adult T-Cell / genetics*
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Molecular Sequence Data
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Mutation*
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Mutation, Missense
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Point Mutation
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Protease Inhibitors / pharmacology
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Protein Structure, Tertiary
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Receptor, Notch1
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Sequence Deletion
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Signal Transduction
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Transcription Factors / chemistry
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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NOTCH1 protein, human
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Protease Inhibitors
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Receptor, Notch1
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Receptors, Cell Surface
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Transcription Factors
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human