Erythropoietin (Ep) dose-response curves for three classes of erythroid progenitors in normal human marrow and in patients with polycythemia vera

Abstract

Three classes of normal human erythropoietic progenitor cells were investigated with respect to their erythropoietin (Ep) sensitivity under various culture conditions. Dose-response curves extending from 0.001 to 10 units Ep/ml indicated that under optimal conditions the formation of very large erythroid colonies or 'bursts' (from primitive BFU-E) required about three times the Ep concentration needed for small bursts (from mature BGU-E) and about five times that needed for the production of small erythroid clusters (from CFU-E). These findings suggest that by the primitive BFU-E stage erythropoietic cells in man have the capacity to respond to EP and that this responsiveness then progressively increases. Removal of the the adherent marrow cell fraction and/or omission of leukocyte-conditioned medium from the cultures resulted in failure to achieve maximum burst formation by primitive BFU-E even in the presence of 10 units Ep/ml. Elimination of these sources of burst-enhancing factors had less effect on the Ep dose-response curve for mature BFU-E, and the effect on CFU-E detection was minimal. These data show that red cell precursors at sequential stages of differentiation also show progressive changes in their response to factors other than Ep that affect burst formation in vitro. Ep dose-response data were also obtained for primitive and mature BFU-E and CFU-E present in specimens from five patients with polycythemia vera (PV). Simple analysis of the curves obtained indicated two coexisting population in this disease: (1) a population of abnormally (hyper) Ep-responsive cells (sensitive to <0.001 units/ml) and (2) a population of cells whose Ep sensitivity in vitro fell within the appropriate normal range. Quantitation of the ratio of phenotypically normal and abnormal progenitors defined in this way showed a progressive increase in favor of the abnormal cells in the later, mature BFU-E and CFU-E compartments. This could reflect a growth advantage in PV of the abnormally Ep-sensitive line proliferating in a low Ep environment. Such an interpretation would also be consistent with the concept that Ep can influence the production of early red cell precursors in man.