Regulation of CD95 expression and CD95-mediated cell death by interferon-gamma in acute lymphoblastic leukemia with chromosomal translocation t(4;11)

The regulatory effects of IFN gamma on CD95 expression and CD95-mediated ce ll death were investigated in three high-risk pro-B acute lymphoblastic leu kemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23) . These leukemias are characteristically refractory to conventional chemoth erapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell d eath in these leukemias are largely unknown. Interferon-gamma (IFN gamma), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low revels of CD95, but were completely resistant to CD95-mediated death. Addition of IFN gamma markedly upregulated CD95 expres sion in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. How ever, after treatment with IFN gamma, only an 11% increase in sensitivity t o CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV 4;11 cells remained resistant. Cycloheximide, but not actinomycin D or bref eldin A, increased CD95-specific cell death only in IFN gamma-treated RS4;1 1 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible r ole for both molecules in the resistance to CD95-mediated cell death. Resis tance of the leukemic blasts to CD95-mediated cell death and the failure of IFN gamma to substantially sensitize the CD95-signaling pathway may contri bute to the highly malignant phenotype of pro-B ALL with translocation t(4; 11).