Fas receptor-Fas ligand system is independent of both CD34 status and chemosensitivity in acute myeloid leukemia

Objective. To determine whether the Fas receptor-Fas ligand (FasR-FasL) sys tem, which triggers apoptosis in sensitive cells, is an important mechanism of cytotoxicity in acute myeloblastic leukemia (AML). Materials and Methods. We investigated FasR expression in primary AML cells and its upregulation by tumor necrosis factor (TNF), as well as the apopto sis induced by anti-Fas antibody and the potential interaction between the FasR-FasL system and the cytotoxic drug daunorubicin (I)NR). Results. FasR was expressed on all 25 AML samples and three normal bone mar row harvests. The intensity of expression was variable (range 1.6-2.1 in no rmal bone marrow CD34(+) cells and 1.5-5.1 in AML cells, median 2.4) and wa s related to the morphologic FAB classification, with the highest expressio n in FAB types M4 and M5 (range 1.6-5.1, median 3.2), No relationship was f ound between FasR expression and expression of the CD34 antigen. FasR was h eterogeneously upregulated in all AML cells on treatment with TNF-alpha. Th e degree of FasH upregulation induced was found to be related to the FAB su btype, with the greatest response observed in immature FAB types M1, M2, an d M6 (range 11.0-207.1%, median 48.7%). Apoptosis could be induced in all A ML samples, but not in normal bone marrow CD34(+)ve cells, by the CH11 anti -FasR antibody, although the response was variable (range 4.1-37.6%, median 16.5%), The monocytic differentiated M4 and M5 AML cells exhibited the gre atest sensitivity to Fas-mediated apoptosis (range 4.4-37.6, median 20.65%) ; however, no relationship was found between sensitivity to Fas-mediated ap optosis and FasR expression or CD34 positivity. Apoptosis in response to DN R was observed in all AML cases; however, sensitivity was heterogeneous and found to be unrelated to FasR expression or sensitivity to Fas-mediated ap optosis, The blocking anti-FasR antibody ZB4 blocked anti-FasR-mediated apo ptosis but had no inhibitory effect on DNR-induced apoptosis in AML blasts. No cytotoxic synergistic effect was demonstrated when anti-FasR antibody w as used in combination with DNR. Conclusion. In AML, DNR induces apoptosis through an Pas-independent pathwa y. However, the induction of apoptosis through the Fas pathway might be a n ovel and effective approach for leukemia immunotherapy, particularly becaus e Fas-mediated apoptosis was noted in CD34(+) and CD34(-) cases. (C) 2000 I nternational Society for Experimental Hematology. Published by Elsevier Sci ence Inc.