High susceptibility of human leukemic cells to Fas-induced apoptosis is restricted to G1 phase of the cell cycle and can be increased by interferon treatment.
In this study, we analyzed the influence of cell cycle status manipulations of leukemic cells on Fas-mediated apoptosis using the GM-CSF-dependent human myeloid leukemia cell line AML-193 as a model. GM-CSF and long-term treatment with interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha) were used to manipulate the cell cycle status. Control cells were GM-CSF deprived, nonproliferating cells. IFN-gamma or IFN-alpha treatment did not induce proliferation in control cells, but resulted in recruitment of cells from resting G(0) phase into activated G(1) phase. Using agonistic anti-Fas antibodies (FAS18), we demonstrated that this shift from G(0) to G(1) was accompanied by a 2.5-fold increase in Fas sensitivity. A similar increase in sensitivity to FAS18 could be obtained by induction of proliferation with GM-CSF. Quantitative FACS analysis of surviving cells after FAS18-induced apoptosis showed deletion of the G(1) compartment, but complete protection of resting G(0) cells. Cells in S or G(2)/M phase were relatively protected against Fas induction. In conclusion, sensitivity to Fas-mediated apoptosis was restricted to cells in G(1) phase of the cell cycle, and can be increased by treatment of cells with interferons. By this mechanism, interferon treatment may render leukemic cells more susceptible to lysis by T cells during immunotherapeutic interventions.
Jedema
I
I
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, The Netherlands.
Barge
R M Y
RM
Willemze
R
R
Falkenburg
J H F
JH
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects* / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D007372:Interferons / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D019014:fas Receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007372:Interferons