Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders

The absolute polycythemias--those with increased red blood cell mass--can be divided into two groups: primary, caused by acquired or inherited mutations leading to a "gain-of-function" abnormalities expressed within the erythroid progenitors; and secondary, due to circulating serum factors, typically erythropoietin, stimulating erythropoiesis. This overview concentrates on the molecular biology of polycythemia vera (PV) discussed in the context of other polycythemic disorders. Recent advances in the regulation of erythropoiesis, as they may relate to polycythemic states, are discussed as a background for those well-defined polycythemic states wherein the molecular defect has not yet been elucidated. A number of cellular abnormalities associated with PV, including the hyperresponsiveness of PV progenitors to many cytokines as well as decreased expression of the thrombopoietin receptor on platelets and increased expression of Bcl-xL, suggest that the PV defect alters a number of cellular functions and is not restricted to cytokine receptor signal transduction. The increasing number of recognized instances of familial incidence of PV suggests that in these families the predisposition for PV is inherited as a dominant trait, and that PV is acquired as a new mutation that leads to a clonal hematopoiesis and may be due to loss of heterozygosity. The existence of these families provides a unique opportunity for isolation of the mutations in the gene leading to PV. Semin Hemaol 38(suppl 2):10-20.