Defective expression of the SHP-1 phosphatase in polycythemia vera

The SHP-1 phosphatase associates with the receptors for erythropoietin, ste m cell factor, and interleukin-3, and negatively regulates the mitogenic si gnals generated during engagement by their respective ligands. The erythroi d progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hype rsensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The de creased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid prog enitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference b etween the two at early colony forming unit-erythroid stage of differentiat ion although polycythemia vera cells showed retarded differentiation kineti cs at late colony forming unit-erythroid stage of differentiation. Furtherm ore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the earl y stages of erythropoiesis. These results indicate an important role for SH P-1 in the regulation of normal human erythroid progenitors and suggest tha t defective expression of the protein may contribute to the pathogenesis of polycythemia vera. (C) 1999 International Society for Experimental Hematol ogy. Published by Elsevier Science Inc.