Bcr-Abl and Signal Transduction

Abstract

The BCR-ABL oncogene is generated by the Philadelphia (Ph) chromosome translocation, fusing the BCR to the ABL gene. The Bcr-Abl fusion protein has constitutive and deregulated tyrosine kinase activity that is critical for transformation of hematopoietic cells. Different leukemia phenotypes are preferentially associated with the three fusion Bcr-Abl proteins (p190, p210, and p230) that may be expressed from the hybrid gene. Cells transformed by Bcr-Abl show activation of mitogenic signaling pathways, inhibition of apoptosis and altered cellular adhesion. CML is characterized by an inevitable progression from a chronic phase to an acute phase called blast crisis. Progression of the disease is related to the acquisition of additional genetic alterations probably associated with genomic instability. This can be a consequence of Bcr-Abl activation or may even represent an ancestral stem cell defect preceding the acquisition of the Ph-chromosome translocation, as recent observations seem to suggest. However, the mechanisms responsible for Bcr-Abl rearrangement remain elusive, although the chromosomal translocation seems to occur relatively frequently in the general population, as evidenced by the detection of rare BCR-ABL fusion transcripts in the leukocytes of healthy individuals.