Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation

Chronic myeloid leukemia (CML) is caused by the Bcr-Abl oncoprotein, the product of the t(9;22) chromosomal translocation that generates the Philadelphia chromosome. Different disease phenotypes are associated with each of the three Bcr-Abl isoforms: P190(Bcr-Abl), p210(Bcr-Abl), and p230(Bcr-Abl) all of which have a constitutively activated tyrosine kinase. Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signaling pathways, inhibition of apoptosis, and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an "indolent" chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.