Biological Properties Of Cml Cells

Compared to their normal counterparts, CML progenitor cells are able to enter the cell cycle in the absence of growth factors,96 although they are not cytokine-inde-pendent.97 Nonetheless, the reduced requirement for external stimuli may lend a growth advantage to CML cells that is sufficient to outcompete normal hematopoiesis over time. There is evidence that autocrine production of IL-3 and granulocyte colony-stimulating factor by CML progenitor cells may be the underlying mechanism.98 In addition to inducing proliferation, Bcr-Abl has been shown to inhibit apoptosis by multiple mechanisms, including upregulation of the antiapoptotic protein Bcl-XL and downregulation of proapoptotic Bim.99-103 A third biological feature that characterizes Bcr-Abl-positive cells is a perturbation of their adhesion to stroma104 and migration in response to chemokines such as SDF-1,105 which may explain extramedullary hematopoiesis. It has been difficult to link certain biological properties to the activation of specific signaling pathways that are activated by Bcr-Abl, and the issue is complicated by the fact that much of the data are derived from studies in cell lines rather than primary CML cells. Proliferation and inhibition of apoptosis are strictly dependent on Bcr-Abl kinase activity, whereas the defects in adhesion and migration are not completely reversible upon inhibition of Bcr-Abl.106 If this is clinically significant in the setting of targeted therapy of CML with imatinib remains to be seen.

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