Genetic Approaches to Defining Signaling by the CML-associated Tyrosine Kinase BCR-ABL

Human chronic myelogenous leukemia (CML) is a cancer that is associated with a specific cytogenetic marker known as the Philadelphia (Ph1) chromosome (Nowell and Hungerford, 1960; Rowley, 1973; reviewed in Kurzrock et al. , 1988). Cells of multiple lineages carry Ph1, suggesting that the disease originates in a pluripotent stem cell. Ph1 is the result of a reciprocal translocation of chromosomes 9 and 22, which results in the fusion of two cellular genes encoding BCR and c-ABL (Shtivelman et al. , 1985; Clark et al. , 1988). The resulting fusion gene (see Figure 1) encodes BCR-ABL, an activated protein tyrosine kinase. The tyrosine kinase activity of BCR-ABL is deregulated when compared to c-ABL (Konopka and Witte, 1985) and is the most essential feature for its transforming activity. In nature two fusion products are detected. P210 BCR-ABL is associated with CML and P185 BCR-ABL is associated with the more aggressive acute lymphocytic leukemia (ALL). The tyrosine kinase activity of P185 is more potent than P210 kinase activity, which also correlates with their respective transforming activities (Lugo et al. , 1990).