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Blood, 1 May 2001, Vol. 97, No. 9, pp. 2596-2603

HEMATOPOIESIS

Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1

Roberta Di Pietro, Paola Secchiero, Rosalba Rana, Davide Gibellini, Giuseppe Visani, Kristi Bemis, Loris Zamai, Sebastiano Miscia, and Giorgio Zauli

From the Institute of Human Morphology, "G. D'Annunzio" University of Chieti; the Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara; the Department of Clinical and Experimental Medicine, Microbiology Section, and "L.A. Seragnoli" Institute of Hematology, University of Bologna; and the Institute of Morphological Sciences, University of Urbino, Italy; and the Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore.

Cytotoxic activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand), used alone or in different combinations with either a low (1.5 Gy) or a high (15 Gy) single dose of ionizing radiation (IR), was investigated on erythroleukemic cells (K562, HEL, Friend, primary leukemic erythroblasts) and on primary CD34+-derived normal erythroblasts. Human recombinant TRAIL alone variably affected the survival/growth of erythroleukemic cells; K562 cells were the most sensitive. Moreover, all erythroleukemic cells were radio-resistant, as demonstrated by the fact that cytotoxicity was evident only after treatment with high-dose (15 Gy) IR. Remarkably, when IR and TRAIL were used in combination, an additive effect was noticed in all erythroleukemic cells. Augmentation of TRAIL-induced cell death by IR was observed with both low and high IR doses and required the sequential treatment of IR 3 to 6 hours before the addition of TRAIL. Conversely, both TRAIL and IR showed a moderate cytotoxicity on primary CD34+-derived normal erythroblasts when used alone, but their combination did not show any additive effect. Moreover, the cytotoxicity of IR plus TRAIL observed in erythroleukemic cells was accompanied by the selective up-regulation of the surface expression of TRAIL-R1 (DR4), and it was completely blocked by the z-Val-Ala-Asp (OMe)-CH2 (z-VAD-fmk) caspase inhibitor. On the other hand, the surface expression of TRAIL-R1 in CD34+-derived normal erythroblasts was unaffected by IR, which induced the up-regulation of the decoy TRAIL-R3. These data demonstrate that treatment with IR provides an approach to selectively sensitize erythroleukemic cells, but not normal erythroblasts, to TRAIL-induced apoptosis through the functional up-regulation of TRAIL-R1.

© 2001 by The American Society of Hematology.
 

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