The Bcr-Abl tyrosine kinase found in Philadelphia chromosome (Ph1)-positive leukaemia is the result of a reciprocal translocation between chromosomes 9 and 22. Depending on the breakpoint of the bcr gene, different isoforms of Bcr-Abl appear and are associated with specific types of leukemias; in chronic myelogenous leukaemia (CML), a 210kDa protein is responsible for a deregulated proliferation and consequently accumulation of myeloid cells and their precursors, whereas in acute lymphocytic leukaemia (ALL) a 185kDa Bcr-Abl protein is the oncogenic counterpart. This chimeric protein not only induces transformation of cell lines, but also regulates cell proliferation and is one of the most potent anti-apoptotic molecules responsible for resistance to a variety of apoptosis-inducing agents. The signalling pathway of apoptosis which may be regulated by Bcr-Abl is still unknown, but our latest findings suggested that Bcr-Abl act at the mitochondrial level, preserving the mitochondria integrity during several apoptogenic stimuli thereby preventing release of cytochrome c and the consequent activation of effector caspases. To investigate the mechanisms whereby Bcr-Abl interferes with the cell apoptotic machinery, we asked where in Fas signalling cascade that Bcr-Abl blocks the apoptogenic signal. For this purpose, HL-60.neo, HL-60.Bcr-Abl, HL-60.Bcl-2 and HL-60.Bcl-xL cells were stimulated with anti-Fas antibodies (CH11), in the presence or not of cycloheximide, and the levels of apoptosis and activation of caspases where compared between wild-type and transfected cells with anti-apoptotic molecules. Our results demonstrate that Bcr-Abl blocks both mitochondria dependent and independent Fas pathway, suggesting that Bcr-Abl has a bigger spectrum of action than Bcl-2 and Bcl-xL.


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