Abstract
Philadelphia (Ph)-positive leukemias invariably contain a chromosomal translocation fusing BCR to ABL. The BCR-ABL protein is responsible for leukemogenesis. Here we show that exposure of bcr-null mutant mice to gram-negative endotoxin led to severe septic shock and increased tissue injury by neutrophils. Neutrophils of bcr (-/-) mice showed a pronounced increase in reactive oxygen metabolite production upon activation and were more sensitive to priming stimuli. Activated (-/-) neutrophils displayed a 3-fold increased p21rac2 membrane translocation compared with (+/+) neutrophils. These results connect Bcr in vivo with the regulation of Rac-mediated superoxide production by the NADPH-oxidase system of leukocytes and suggest a link between Bcr function and the cell type affected in Ph-positive leukemia.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actin Cytoskeleton / physiology
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Animals
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Endotoxins / toxicity
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Female
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GTP-Binding Proteins / biosynthesis
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GTP-Binding Proteins / metabolism
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Gene Targeting
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Mutation / physiology*
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Neutropenia / chemically induced
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Neutropenia / immunology
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Neutrophil Activation*
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Neutrophils / metabolism*
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Oncogene Proteins / genetics*
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Oncogene Proteins / physiology
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Protein-Tyrosine Kinases*
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Proto-Oncogene Proteins c-bcr
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Proto-Oncogene Proteins*
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Respiratory Burst / immunology*
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Shock, Septic / chemically induced
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Shock, Septic / immunology
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Shock, Septic / pathology
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Superoxides / metabolism
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Toxemia / chemically induced
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Toxemia / immunology
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Toxemia / pathology
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rac GTP-Binding Proteins
Substances
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Endotoxins
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Lipopolysaccharides
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Oncogene Proteins
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Proto-Oncogene Proteins
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Superoxides
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Protein-Tyrosine Kinases
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Bcr protein, mouse
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Proto-Oncogene Proteins c-bcr
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GTP-Binding Proteins
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rac GTP-Binding Proteins