Abstract
Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.
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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Animals
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Calcium-Binding Proteins
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Cell Communication / physiology
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Cell Culture Techniques / methods
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Coculture Techniques
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Genes, T-Cell Receptor gamma / genetics
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Transplantation
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Oligopeptides / pharmacology
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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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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / physiopathology*
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / physiology*
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Stromal Cells / cytology
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Stromal Cells / physiology
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Tumor Cells, Cultured
Substances
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Calcium-Binding Proteins
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DLK1 protein, human
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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NOTCH1 protein, human
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Oligopeptides
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Receptor, Notch1
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benzyloxycarbonyl-leucyl-leucyl-norleucinal
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Amyloid Precursor Protein Secretases