Abstract
The nonreceptor protein spleen tyrosine kinase (Syk) is a key mediator of signal transduction in a variety of cell types, including B lymphocytes. We show that deregulated Syk activity allows growth factor-independent proliferation and transforms bone marrow-derived pre-B cells that are then able to induce leukemia in mice. Syk-transformed pre-B cells show a characteristic pattern of tyrosine phosphorylation, increased c-Myc expression, and defective differentiation. Treatment of Syk-transformed pre-B cells with a novel Syk-specific inhibitor (R406) reduces tyrosine phosphorylation and c-Myc expression. In addition, R406 treatment removes the developmental block and allows the differentiation of the Syk-transformed pre-B cells into immature B cells. Because R406 treatment also prevents the proliferation of c-Myc-transformed pre-B cells, our data indicate that endogenous Syk kinase activity may be required for the survival of pre-B cells transformed by other oncogenes. Collectively, our data suggest that Syk is a protooncogene involved in the transformation of lymphocytes, thus making Syk a potential target for the treatment of leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adoptive Transfer
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism*
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B-Lymphocytes / transplantation
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Benzamides
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Line
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Cell Proliferation / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Humans
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Imatinib Mesylate
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Intercellular Signaling Peptides and Proteins / pharmacology
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Intercellular Signaling Peptides and Proteins / physiology
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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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 / genetics
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Leukemia / pathology
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Leukemia / therapy
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Oxazines / pharmacology
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Phospholipase C gamma / genetics
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Phospholipase C gamma / metabolism
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Phosphorylation / drug effects
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Pyridines / pharmacology
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Pyrimidines / pharmacology
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Receptors, Antigen, B-Cell / genetics
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Spleen / drug effects
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Spleen / metabolism
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Spleen / pathology
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Syk Kinase
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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B cell linker protein
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Benzamides
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DNA-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
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Oxazines
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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Pyridines
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Pyrimidines
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Rag2 protein, mouse
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Receptors, Antigen, B-Cell
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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Phospholipase C gamma