ABSTRACT
Studies carried out over 20 years ago first linked the ABL kinases to the development of cancer.1 Oncogenic activation of c-ABL was initially shown to occur as a result of structural alterations of the c-ABL protein. Four naturally occurring c-ABL-derived oncogenes have been identified to date. They are the v-abl oncogene of the Abelson murine leukemia virus (AMuLV),2 the v-abl oncogene of the Hardy-Zuckerman-2 feline sarcoma virus (HZ2-FSV),3 the BCR/ABL chimeric oncogene of Philadelphia chromosome-positive human leukemias,4,5 and the TEL/ABL chimeric oncogene associated with acute lymphoblastic and myeloid human leukemias.6,7 The BCR/ABL and TEL/ABL proteins arise as a consequence of chromosomal translocation events that fuse N-terminal sequences from the BCR and TEL genes, respectively, to sequences upstream of the second exon of c-ABL.4,5,7 The N-terminal sequences derived from the BCR and TEL proteins provide oligomerization domains and other sequences important for the oncogenicity of the chimeric proteins. Interestingly, unlike
the normal c-ABL protein, which localizes to nuclear and cytosolic compartments, the majority of the oncogenic ABL proteins localize predominantly to the cytoplasm.8,9 This chapter will focus primarily on our current understanding of the contribution of specific domains in BCR/ABL to oncogenesis and the identification of signaling pathways employed by BCR/ABL to transform cells.
