Genetic Approaches to Defining Signaling by the CML-associated Tyrosine Kinase BCR-ABL
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Excerpt
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; for review, see 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 Fig. 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...
