Defects in signal transduction pathways in chronic B lymphocytic leukemia cells.
B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells are refractory to many of the signals which activate normal B cells but are stimulated to proliferate by tumor necrosis factor (TNF). Cell signalling by TNF is mediated in part by the induction of the transcription factor families AP-1 and NF-kappa B. In some cellular contexts, these factors play a role in regulating cell cycle transit. AP-1 binds DNA as dimers of jun and fos family proteins and is regulated by a cascade of protein kinases which eventually activate a mitogen-activated protein kinase (MAP kinase) and also by protein kinase C. Three pathways have been implicated in the activation of NF-kappa B by extracellular ligands. 1, the activation of protein kinase C by diacylglycerol generated by ligand-mediated activation of phosphatidylcholine hydrolysis, 2, stimulation of specific protein kinases by ceramide generated following activation of a sphingomyelinase by diacylglycerol and 3, a novel pathway involving ligand-induced generation of free radical species. In B-CLL and HCL cells, the generation of nuclear-localized c-jun and c-fos proteins (components of AP-1) in response to TNF or PMA appears to be blocked. Whereas PMA failed to induce NF-kappa B in these cells, this factor was readily induced by TNF. TNF induction of NF-kappa B was abolished by antioxidants, suggesting involvement of the free radical pathway. The data discussed here suggest defects in coupling of some protein kinase C-dependent pathways in B-CLL and HCL cells and that TNF is able to bypass these blocks by the activation of NF-kappa B via a free radical-dependent pathway which is independent of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
Jabbar
S A
SA
Department of Haematology, Royal Free Hospital and Medical School, London, UK.
Hoffbrand
A V
AV
Wickremasinghe
R G
RG
D000818:Animals; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000503:physiopathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
D016328:NF-kappa B; D018808:Transcription Factor AP-1