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.
The role of FAS-mediated apoptosis in chronic myelogenous leukemia.
SELLERI, Carmine;
2000-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.