Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction

Ineffective erythropoiesis in myelodysplasia is characterized by a defect i n erythroid progenitor growth and by abnormal erythroid differentiation. In creased apoptosis of erythroid, granulocytic and megakaryocytic lineages is thought to account for cytopenias. Erythropoietin (Epo)-induced BFU-E and CFU-E growth was studied in 25 myelodysplastic syndrome (MDS) marrow specim ens and found to be drastically diminished. To investigate the functionalit y of Epo-R in MDS marrow, we focused on Epo-induced STAT5 activation. Epo w as able to stimulate STAT5 DNA binding activity in all normal and 12/24 MDS marrows tested, with no correlation between the level of STAT5 activation and the development of erythroid colonies in response to Epo. in contrast. impaired proliferation of erythroid progenitors was related to an Increased expression of the transmembrane mediator of apoptotic cell death Fas/CD95 on the glycophorin A(+) subpopulation, Therefore we conclude that the stimu lation of pro-apoptotic signals rather than the defect of anti-apoptotic pa thways resulting from Epo-stimulated Jak2-STAT5 pathway predominantly accou nts for ineffective erythropoiesis in myelodysplasia.