Signal transduction pathways involved in BCR-ABL transformation

Abstract

BCR-ABL is an oncogenic fusion gene found in patients with chronic myelogenous leukaemia (CML) and acute lymphocytic leukaemia whose oncogenic potential has been demonstrated using in vitro and in vivo model systems. Current research efforts are focused on defining the mechanism by which BCR-ABL transforms cells, with a view toward applying insights from these studies to the treatment of CML patients. BCR-ABL contains tyrosine residues, an SH2 domain, an SH3 domain, and proline-rich sequences. The presence of so many protein-protein interaction domains raises the possibility of multiple contacts with cellular signal transduction pathways. Indeed, BCR-ABL is reported to bind and/or phosphorylate more than 20 proteins. Many of these can be directly linked to signal transduction pathways based on defined roles in other systems, but others have no known function. As the list of such proteins grows, it is critical to define the role of each in the leukaemogenic activity of BCR-ABL. This review summarizes current views of the mechanism of BCR-ABL transformation with emphasis on the substrates and signal transduction pathways affected by its tyrosine kinase activity.