The role of FAS-mediated apoptosis in chronic myelogenous leukemia

Clinical observation and laboratory evidence suggest that immune mechanisms play an important role in the natural control of evolution of the Ph+ clone in chronic phase as well as during progression of chronic myelogenous leukemia (CML). The understanding of these mechanisms could facilitate development of innovative therapeutic approaches. Due to bcr-abl translocation, CML cells carry an intrinsic resistance to apoptotic signals. However, resistance to apoptosis is not absolute and can be overcome through enhancement of immune-mediated pathways, e.g., during graft vs. leukemia reaction after allogeneic bone marrow transplantation, or during interferon-alpha (IFN-alpha) therapy. Among the effector mechanisms, T-lymphocyte-mediated killing of target cells via Fas-receptor (Fas-R) triggering plays an important role in the elimination of malignant cells, including CML cells. Although CML Ph+ progenitor cells express Fas-R, the expression levels are variable and do not correlate with clinical parameters. In addition, CML progenitor cells also express functional Fas-ligand (Fas-L), which may be an important immune surveillance escape factor. IFN-alpha can greatly upmodulate Fas-R expression, an effect that seems to be more pronounced in CML compared to normal cells, while Fas-L expression levels are not affected by IFN-alpha, thereby improving their susceptibility to elimination by the immune system. Responsiveness to Fas-induced apoptosis following stimulation with IFN-alpha correlates with the clinical effects of IFN-alpha therapy. This effect seems to be associated with decreased bcr-abl protein levels, which are influenced by Fas via posttranscriptional modulation. In comparison to the chronic phase, CML cells derived from patients in blast crisis are refractory to Fas-mediated apoptosis, regardless of the expression levels of Fas, suggesting that an immune-mediated selection pressure could result in acquisition of Fas-resistance. In the future, enhancement of immunological recognition and elimination of CML cells may prove to be an effective therapeutic approach directed towards the cure of CML.