The Philadelphia chromosome translocation (t(9;22)) results in the molecular 
juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on 
chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous 
leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has 
constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic 
activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein 
kinases were thought to be poor therapeutic targets because of their ubiquitous 
nature and crucial role in many normal physiologic processes. However, the 
advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, 
Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer 
kinase inhibitors could be specific. This agent has shown striking activity in 
chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell 
factor receptor) and platelet-derived growth factor receptor. In addition, it 
has shown similar impressive responses, with little host toxicity, in 
gastrointestinal stromal tumors, which harbor activating Kit mutations, and in 
tumors with activated platelet-derived growth factor receptor. The studies of 
imatinib mesylate provide proof-of-principle for using aberrant kinases as a 
therapeutic target and are a model for the promise of molecular therapeutics. 
This paper reviews the current knowledge on the function of Bcr-Abl and its 
normal counterparts (Bcr and Abl), as well as the impact of this knowledge on 
the development of a remarkably successful targeted therapy approach.