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+ clon e in chronic phase as well as during progression of chronic myelogenous leu kemia (CML), The understanding of these mechanisms could facilitate develop ment of innovative therapeutic approaches. Due to bcr-abl translocation, CM L cells carry an intrinsic resistance to apoptotic signals. However, resist ance to apoptosis is not absolute and can be overcome through enhancement o f immune-mediated pathways, e.g., during graft vs, leukemia reaction after allogeneic bone marrow transplantation or during interferon-alpha (IFN-alph a) therapy. Among the effector mechanisms, T-lymphocyte-mediated killing of target cells via Fas-receptor (Fas-R) triggering plays an important role i n 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 a lso express functional Fas-ligand (Fas-L), which may be an important immune surveillance escape factor. IFN-alpha can greatly upmodulate Fas-R express ion, an effect that seems to be more pronounced in CML compared to normal c ells, while Fas-L expression levels are not affected by IFN-alpha, thereby improving their susceptibility to elimination by the immune system. Respons iveness to Fas-induced apoptosis following stimulation with IFN-alpha corre lates with the clinical effects of IFN-alpha therapy. This effect seems to be associated with decreased bcr-ablprotein 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-med iated apoptosis, regardless of the expression levels of Fas, suggesting tha t an immune-mediated selection pressure could result in aquisition of Fas-r esistance. In the future, enhancement of immunological recognition and elim ination of CML cells may prove to be an effective therapeutic approach dire cted towards the cure of CML.