title: Vanadate elevates fetal hemoglobin in human erythroid precursors by inhibiting cell maturation.
abstract: Increased fetal hemoglobin (HbF) in erythroid precursors of patients with beta-hemoglobinopathies (sickle cell anemia and beta-thalassemia), in which adult hemoglobin synthesis is defective, ameliorates the clinical symptoms of the underlying diseases. The production of erythroid precursors depends on the action of erythropoietin (EPO), which prevents their apoptosis and stimulates their proliferation. EPO binds to its surface receptor, induces its homodimerization, and initiates a cascade of phosphorylation and dephosphorylation of a series of proteins by kinases and phosphatases, respectively. Vanadate inhibits various phosphatases, including those that are involved in the EPO pathway, thereby intensifying the signal. In this study, we investigated the effect of vanadate on the proliferation and maturation of human erythroid precursors in culture. When vanadate was added to cells derived from normal donors, cell maturation was delayed, as indicated by cell morphology, cell growth kinetics, the rate of appearance of hemoglobin-containing cells, and the expression of surface antigens (CD117, CD71, and glycophorin A). Analysis by high-performance liquid chromatography and flow cytometry of the hemoglobin profile of vanadate-treated normal cells revealed a higher proportion of HbF than was found in untreated cells. When vanadate was added to cells derived from patients with beta-thalassemia, a significant increase in HbF was observed. The results suggest that intensification of the EPO signal by vanadate results in maturation arrest and increased HbF production. Thus, inhibitors that are more specific and less toxic than vanadate may present a novel option for elevating HbF in patients with beta-hemoglobinopathies, as well as for intensifying the EPO response in other forms of anemia.
authors.affiliation: Department of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Amoyal
authors.forename: Eugenia
authors.initials: E
authors.lastname: Prus
authors.forename: Eitan
authors.initials: E
authors.lastname: Fibach
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018955:CD36 Antigens / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism*; D005434:Flow Cytometry; D006021:Glycophorins / Q000032:analysis; D006801:Humans; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011990:Receptors, Transferrin / Q000032:analysis; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D018955:CD36 Antigens; C068126:CD71 antigen; D006021:Glycophorins; D011990:Receptors, Transferrin; D014638:Vanadates; D005319:Fetal Hemoglobin; D019009:Proto-Oncogene Proteins c-kit