Signal Transduction Pathways in BCR-ABL Transformed Cells

ConclusionsThe Bcr-Abl oncoprotein affects and perturbs several signal transduction pathways within the leukemic cell. Based on mouse leukemia model studies, the Ras pathway is critically required for the onset of leukemia in these mice. The IL-3/GM-CSF- receptor pathways are also critically involved. Stimulation of secretion of these cytokines provide an autocrine growth mechanism. However in parallel, independent activation of both the Jak2 and Stat5 pathways are also involved, although critical experiments in mouse models are needed to verify their importance to the leukemia syndrome. Other interesting alterations of signaling proteins also take place in Bcr-Abl positive leukemia cells. For example, reducing the activity of p53 occurs by a unique translational control mechanism that increases the synthesis of Mdm2, a negative regulator of p53 [40]. Another translational control affect is also mediated by Bcr-Abl. Thus, Bcr-Abl blocks expression of the transcription factor C/EBPα [41], which is required for initiating myeloid differentiation toward granulocytes. Bcr-Abl expression also increases the efficiency of DNA repair mechanisms [43], prolongs the cell cycle by blocking cells at the G2/M phase checkpoint, and stimulates the production of proapoptotic factors of the Bcl-2 family members, thereby providing an environment for drug/radiation resistance. In addition, the Bcr-Abl tyrosine kinase in aptly suited to functionally reduce its cellular inhibitor, Bcr, by a process of tyrosine phosphorylation [24,25]. Thus, the oncogenic effects of the Bcr-Abl oncoprotein can be strongly inhibited by modest over-expression of a cDNA of Bcr, either first exon sequences or the full length BCR sequence. Because of these findings discussed above, further investigations are warranted to develop new treatment strategies to enhance the effects of Gleevec with Bcr and other gene products for the therapy of CML [71].