BCRABL signaling and CML pathogenesis

BCR-ABL functions as a constitutively activated tyrosine kinase and significant advances have been made in determining the signaling pathways that are activated by BCR-ABL kinase activity (Figure 7.3). Numerous substrates and binding partners have been identified and current efforts are directed at linking these pathways to the specific pathological defects that characterize CML. The pathological defects identified in CML cells include increased proliferation or decreased apoptosis of a hematopoietic stem or progenitor cell, leading to a massive increase in myeloid cell numbers. Since patients have circulating immature myeloid progenitors, it has been postulated that there is a defect in the adherence of myeloid progenitors to marrow stroma. An example of a cellular pathway that links to an increased proliferative rate is activation of the RAS pathway. STAT-5-mediated upregulation of the anti-apoptotic molecule BCLxl and the phosphorylation and inactivation of the pro-apoptotic molecule BAD by AKT are postulated to lead to a protection from programmed cell death. CML cells also exhibit reduced adhesion to fibronectin, possibly as a downstream effect of CRKL phosphorylation. Despite the seemingly endless expansion of the list of pathways activated by BCR-ABL and the increasing complexity that is being revealed in these pathways, all of the transforming functions of BCR-ABL are dependent on its tyrosine kinase activity.

Fig. 7.3 Signaling pathways affected by BCR-ABL expression

Fig. 7.3 Signaling pathways affected by BCR-ABL expression

Bone Marrow Stroma Bcr Abl
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