Phosphatidyl inositol signaling by BCR/ABL: opportunities for drug development

The t(9;22) translocation associated with chronic myelogenous leukemia (CML) fuses the c-ABL gene on chromosome 9 with the BCR gene on chromosome 22, resulting in the production of one or more of a family of chimeric oncoproteins, p190, p210, or p230 BCR/ABL. These proteins have activated ABL kinase activity and are located in the cytoplasm of CML cells, predominantly in the cytoskeleton. Recent studies have led to the identification of numerous potential substrates for BCR/ABL, including many proteins that normally function in signal transduction pathways downstream from hematopoietic growth factor receptors. BCR/ABL is autophosphorylated on tyrosine residues and attracts a variety of adapter proteins and other signaling proteins, setting up large signaling complexes that ultimately result in growth. viability, and adhesion signals. Using new in vitro and animal model systems, it is now becoming possible to link specific signaling pathways to biological abnormalities in CML cells. Furthermore, the relative importance of some BCR/ABL-activated pathways is becoming clear. In vivo studies in certain lines of transgenic mice suggest that the antiapoptotic effect of Bcr/Abl is more important than previously thought. Our current studies indicate important roles for phosphoinositide 3-kinase/Akt and for STAT molecules. As a result of these more detailed biochemical analyses of BCR/ABL function, new targets for future drug development have been identified.