TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis

The impact of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on normal hematopoietic development was investigated using adult p eripheral blood CD34(+) hematopoietic progenitor cells, induced to differen tiate along the erythroid, megakaryocytic, granulocytic, and monocytic line ages by the addition of specific cytokine cocktails. TRAIL selectively redu ced the number of erythroblasts, showing intermediate levels of glycophorin A (glycophorin A(interm)) surface expression, which appeared in liquid cul tures supplemented with stem cell factor + interleukin 3 + erythropoietin a t days 7-10. However, neither immature (day 4) glycophorin A(dim) erythroid cells nor mature (day 14) glycophorin A(bright) erythroblasts were sensiti ve to TRAIL-mediated apoptosis, Moreover, preexposure to TRAIL significantl y decreased the number and size of erythroid colonies in semisolid assays, These adverse effects of TRAIL were selective for erythropoiesis, as TRAIL did not significantly influence the survival of cells differentiating along the megakaryocytic, granulocytic, or monocytic lineages, Furthermore, TRAI L was detected by Western blot analysis in lysates obtained from normal bon e marrow mononuclear cells, These findings indicate that TRAIL acts in a li neage- and stage of differentiation-specific manner, as a negative regulato r of normal erythropoiesis. (C) 2000 by The American Society of Hematology.