Abstract
Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell-derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Axl Receptor Tyrosine Kinase
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology
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B-Lymphocytes / pathology
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Benzocycloheptenes / pharmacology
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Binding Sites
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Coculture Techniques
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitriles / pharmacology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Quinolines / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism*
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Stromal Cells / drug effects
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Triazoles / pharmacology
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism
Substances
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Aniline Compounds
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Benzocycloheptenes
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitriles
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Quinolines
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Triazoles
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bemcentinib
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bosutinib
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Protein Kinases
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Receptor Protein-Tyrosine Kinases
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src-Family Kinases
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Axl Receptor Tyrosine Kinase
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AXL protein, human