Increased neutrophil respiratory burst in bcr-null mutants.
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.
Voncken
J W
JW
Department of Pathology, Childrens Hospital of Los Angeles 90027.
van Schaick
H
H
Kaartinen
V
V
Deemer
K
K
Coates
T
T
Landing
B
B
Pattengale
P
P
Dorseuil
O
O
Bokoch
G M
GM
Groffen
J
J
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D018390:Gene Targeting; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology*; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D016897:Respiratory Burst / Q000276:immunology*; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D014115:Toxemia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D020744:rac GTP-Binding Proteins
D004731:Endotoxins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D013481:Superoxides; D011505:Protein-Tyrosine Kinases; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins