Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCdelta and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCdelta downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology*
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Caspase 3 / metabolism
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Cell Survival / drug effects
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Cell Survival / genetics
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Gene Expression Regulation, Neoplastic*
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
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Ligands
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphorylation
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Proteasome Endopeptidase Complex / metabolism*
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Protein Kinase C-delta / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Syk Kinase
Substances
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Intracellular Signaling Peptides and Proteins
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Ligands
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Myeloid Cell Leukemia Sequence 1 Protein
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Protein Kinase C-delta
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Caspase 3
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Proteasome Endopeptidase Complex