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 in erythroid progenitor growth and by abnormal erythroid differentiation. Increased 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 specimens and found to be drastically diminished. To investigate the functionality of Epo-R in MDS marrow, we focused on Epo-induced STAT5 activation. Epo was 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 stimulation of pro-apoptotic signals rather than the defect of anti-apoptotic pathways resulting from Epo-stimulated Jak2-STAT5 pathway, predominantly accounts for ineffective erythropoiesis in myelodysplasia.
Fontenay-Roupie
M
M
Département d'Hématologie, AP-HP, INSERM U363, Université René Descartes, Hôpital Cochin, Paris, France.
Bouscary
D
D
Guesnu
M
M
Picard
F
F
Melle
J
J
Lacombe
C
C
Gisselbrecht
S
S
Mayeux
P
P
Dreyfus
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015672:Erythroid Precursor Cells; D004920:Erythropoiesis / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006021:Glycophorins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000097:blood* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D018952:Antigens, CD34; D006021:Glycophorins; D009097:Multienzyme Complexes; D017467:Receptors, Erythropoietin; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex