BCR-ABL ACTIVATES PATHWAYS MEDIATING CYTOKINE INDEPENDENCE AND PROTECTION AGAINST APOPTOSIS IN MURINE HEMATOPOIETIC-CELLS IN A DOSE-DEPENDENT MANNER

The hallmark of chronic myeloid leukemia (CML) is the chimeric tyrosin e kinase oncogene bcp - abl. Since expression of bcr - abl mRNA freque ntly increases with disease progression and a duplication of the Phila delphia chromosome (harbouring the bcr - abl hybrid locus) represents the most frequent karyotypic abnormality in acute phase CML, we hypoth esized that the level of BCR - ABL protein may affect the disease phen otype. Therefore, the biological effects of high and low levels of BCR - ABL expression were compared in growth factor-dependent and -indepe ndent myeloid and lymphoid cell lines. Our results demonstrated that l ow levels of BCR - ABL were sufficient to render these cell lines grow th factor independent and tumorigenic, but higher levels were mandator y for additional protection against apoptotic stimuli. The provision o f growth factor or an activated ras oncogene did not afford the same d egree of protection as high levels of BCR - ABL and there were qualita tive differences between the survival signals mediated by BCR - ABL an d Bcl-2. These results have enabled us to establish a dose-dependent h ierarchy of BCR - ABL induced biological effects, thus distinguishing the activation of pathways mediating protection from cytokine withdraw al from those protecting against other apoptotic stimuli.