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Apoptotic mechanisms in the control of normal and pathologic erythropoiesis Volume 6, issue 6, Novembre - Décembre 2000

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Département d'hématologie et oncologie, Istituto superiore di sanità, viale Regina Elena 299, 00161 Rome, Italie.

In mammals, red blood cells form in the bone marrow within anatomical units called erythroblastic islands. These units include macrophages surrounded by erythroblasts at different stages of maturation. The proliferation and survival of these erythroblasts depend on the presence of erythropoietin. Erythropoietin sustains erythroid cell survival through Stat5 which is required for the expression of the anti-apoptotic factor Bcl-XL and the transcription factor GATA-1. Although death receptors are expressed and used by many cell types, their potential role in the control of erythropoiesis is being elucidated. Fas antigen is expressed in all stages throughout the maturation of human erythroid cells, whereas Fas Ligand (FasL) is expressed only by more mature erythroblasts. This observation allowed for a model where mature erythroblasts participate in a negative-feedback loop to inhibit the formation of red blood cells by activating Fas/FasL system in immature erythroblasts. The biochemical consequences of the activation of the Fas/FasL system in erythroid cells consist in the activation of some caspases (particularly, caspase 3, 7 and 8) resulting in caspase-mediated degradation of the transcription factor GATA-1 and possibly of other erythroid transcription factors, a phenomenon associated with impaired erythroblast maturation. According to this observation it was proposed that caspase-mediated cleavage of some erythroid transcription factors may therefore represent an important negative control mechanism in erythropoiesis. These findings may have also some important implications for the understanding of dyserythropoiesis associated with some pathological conditions, particularly, myelodysplasia and aplastic anemia.