Abstract
Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and γ-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell-mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / genetics*
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B-Lymphocytes / pathology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / physiology*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Calcium-Binding Proteins / physiology
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Cell Communication / genetics
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Cell Communication / physiology
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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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Intercellular Signaling Peptides and Proteins / physiology
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Jagged-1 Protein
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Jagged-2 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / physiology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Receptors, Notch / physiology*
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Serrate-Jagged Proteins
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Signal Transduction / genetics
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Signal Transduction / physiology
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Stromal Cells / metabolism
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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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JAG1 protein, human
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JAG2 protein, human
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Jagged-1 Protein
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Jagged-2 Protein
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Membrane Proteins
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NOTCH3 protein, human
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NOTCH4 protein, human
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Proto-Oncogene Proteins
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Notch
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Serrate-Jagged Proteins