In vitro erythropoiesis in polycythemia vera and other myeloproliferative disorders.

PV is a myeloproliferative disorder characterized by an elevated hematocrit and red blood cell mass. In vitro hematopoietic culture systems have been used extensively to characterize the cellular defect in PV. Erythroid progenitor cells from PV patients exhibit characteristic endogenous erythroid colony growth in serum-containing semisolid culture medium. These endogenous erythroid colonies can be used as a diagnostic tool to distinguish PV from other myeloproliferative disorders and secondary erythrocytosis. Both EPO independence and exquisite EPO sensitivity are mechanism which have been proposed to explain the growth of endogenous colonies. In contrast with normal erythroid progenitor cells which have both high and low affinity EPO-R, PV erythroid cells have only low affinity EPO-R, Molecular analyses did not reveal mutations in the PV EPO-R. These findings have failed to clarify the role of EPO in the etiology of PV. PV hematopoietic progenitor cells also exhibit increased sensitivity to the hematopoietic growth factors GM-CSF, IL-3, and SCF. As with EPO-R studies, examination of IL-3 and SCF receptors on PV erythroid cells has not identified mechanisms underlying the observed increased sensitivities to these hematopoietic growth factors. The recent development of a truly serum-free culture system has led to the observation that PV progenitor cells are more than 100-fold more sensitive to IGF-1 than are normal progenitor cells. In addition, the IGF-1 receptor on PV progenitor cells exhibits increased basal phosphorylation and a hypersensitivity and hyperresponsiveness to IGF-1 with respect to tyrosine phosphorylation. Thus in PV, hypersensitivity to several hematopoietic growth factors may result in hyperproliferation of hematopoietic cells. This hypersensitivity ma be due to a defective intracellular mechanism common to these hematopoietic growth factors.