The susceptibility of Philadelphia chromosome positive cells to FAS-mediated apoptosis is not linked to the tyrosine kinase activity of BCR-ABL.
We investigated whether inhibition of the BCR-ABL tyrosine kinase by the CGP57418B compound would render chronic myeloid leukaemia (CML) cells susceptible to Fas (CD95, Apo-1)-mediated cell death. Only two (AR230 and SD1) out of 10 BCR-ABL positive cell lines were found to express the CD95 protein. No change in Fas expression was observed in any of the 10 cell lines after 48 h exposure to CGP57418B. AR230 cells were resistant and SD1 cells were partially resistant to Fas-mediated apoptosis induced by ligation of the Fas receptor to an anti-Fas IgM antibody. Pre-incubation with 1 microM CGP57418B did not change the susceptibility of these cell lines to Fas-mediated cell death. Similar results were observed in experiments with CD34+ cells from CML patients and from normal individuals. The data suggest that, in contrast to some cytotoxic drugs, the CGP57148B tyrosine kinase inhibitor utilizes a pathway other than the CD95 system in order to induce apoptosis in CML cells.
Gora-Tybor
J
J
LRF Centre for Adult Leukaemia, Department of Haematology, ICSTM, Hammersmith Hospital, London, UK.
Deininger
M W
MW
Goldman
J M
JM
Melo
J V
JV
D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001549:Benzamides; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D018952:Antigens, CD34; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D019014:fas Receptor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl