Abstract
Deregulated Notch signaling occurs in the majority of human T-ALL. During normal lymphoid development, activation of the Notch signaling pathway poses a T-cell fate on hematopoietic progenitors. However, the transcriptional targets of the Notch pathway are largely unknown. We sought to identify Notch target genes by inducing Notch signaling in human hematopoietic progenitors using two different methods: an intracellular signal through transfection of activated Notch and a Notch-receptor dependent signal by interaction with its ligand Delta1. Gene expression profiles were generated and evaluated with respect to expression profiles of immature thymic subpopulations. We confirmed HES1, NOTCH1 and NRARP as Notch target genes, but other reported Notch targets, including the genes for Deltex1, pre-T-cell receptor alpha and E2A, were not found to be differentially expressed. Remarkably, no induction of T-cell receptor gene rearrangements or transcription of known T-cell specific genes was found after activation of the Notch pathway. A number of novel Notch target genes, including the transcription factor TCFL5 and the HOXA cluster, were identified and functionally tested. Apparently, Notch signaling is essential to open the T-cell pathway, but does not initiate the T-cell program itself.
MeSH terms
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Animals
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Animals, Outbred Strains
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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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Cell Lineage / physiology*
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Cells, Cultured
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Fetal Blood / cytology
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Gene Expression Profiling
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Phosphoproteins / genetics
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Proteins / genetics
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Proteins / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Stromal Cells
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T-Lymphocytes / cytology
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T-Lymphocytes / physiology*
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Transcription Factor HES-1
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Transcription Factors
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Transfection
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Triglycerides / pharmacology
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gamma-Aminobutyric Acid / analogs & derivatives
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gamma-Aminobutyric Acid / pharmacology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Homeodomain Proteins
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Hoxa5 protein, mouse
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Intracellular Signaling Peptides and Proteins
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NOTCH1 protein, human
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Nrarp protein, mouse
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Phosphoproteins
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Proteins
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Receptor, Notch1
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TCFL5 protein, human
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Transcription Factor HES-1
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Transcription Factors
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Triglycerides
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HES1 protein, human
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gamma-Aminobutyric Acid
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1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol