An Activating Mutation in the ATP Binding Site of the ABL Kinase Domain

A number of structural alterations have been shown to activate the leukemogenic potential of the ABL oncogene, but there is little understanding of the regulatory mechanisms that are subverted by such changes. We have used directed mutagenesis to examine a potential regulatory motif in cABL, which could directly influence ABL tyrosine kinase activity. A tyrosine to phenylalanine substitution within the ATP binding fold of the ABL kinase domain is sufficient to activate cABL enzymatic activity, and the mutant protein will alleviate growth factor dependence when expressed in the BA/F3 cell line. This growth promotion is dependent upon the structure of the amino terminus of the protein, and the ABL mutation will cooperate with certain BCR sequences in BCR/ABL fusion proteins to deregulate ABL kinase activity.