Abstract
Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.
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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Alleles
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Animals
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Apoptosis
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Blotting, Northern
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Blotting, Western
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Cell Cycle
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Cell Division
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Cell Line
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Cell Line, Transformed
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Chromosome Mapping
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Down-Regulation
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Genes, Dominant
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Genes, Reporter
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Green Fluorescent Proteins
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Humans
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Luminescent Proteins / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / metabolism*
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Mice
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Models, Biological
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Nuclear Proteins / metabolism
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Peptides / chemistry
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Plasmids / metabolism
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Precipitin Tests
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Presenilin-1
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Protein Binding
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Protein Structure, Tertiary
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Receptor, Notch1
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Receptors, Cell Surface*
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Receptors, Notch
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Recombinant Fusion Proteins / metabolism
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Retroviridae / genetics
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Signal Transduction*
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T-Lymphocytes / cytology*
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Time Factors
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Trans-Activators
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Transcription Factors*
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Transduction, Genetic
Substances
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DNA-Binding Proteins
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Luminescent Proteins
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MAML1 protein, human
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Membrane Proteins
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NOTCH1 protein, human
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Notch1 protein, mouse
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Nuclear Proteins
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PSEN1 protein, human
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Peptides
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Presenilin-1
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Receptor, Notch1
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Receptors, Cell Surface
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Receptors, Notch
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Recombinant Fusion Proteins
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Trans-Activators
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Transcription Factors
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Green Fluorescent Proteins