TY - JOUR
T1 - Defective expression of the SHP-1 phosphatase in polycythemia vera
AU - Wickrema, Amittha
AU - Chen, Fei
AU - Namin, Farid
AU - Yi, Taolin
AU - Ahmad, Sarfraz
AU - Uddin, Shahab
AU - Chen, Yi Hsiang
AU - Feldman, Lawrence
AU - Stock, Wendy
AU - Hoffman, Ronald
AU - Platanias, Leonidas C.
N1 - Funding Information:
Supported by grants 97-16 (to AW) and 93-24 (to LCP) from the American Cancer Society Illinois Division and by a grant from William B. Keck Foundation to the Center for Molecular Hematopoiesis, University of Illinois at Chicago.
PY - 1999/7
Y1 - 1999/7
N2 - The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid 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-hypersensitivity 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 decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit- erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, 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 early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.
AB - The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid 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-hypersensitivity 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 decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit- erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, 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 early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.
KW - Erythroid progenitors
KW - Polycythemia vera
KW - SHP-1
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U2 - 10.1016/S0301-472X(99)00043-0
DO - 10.1016/S0301-472X(99)00043-0
M3 - Article
C2 - 10390187
AN - SCOPUS:0033019186
VL - 27
SP - 1124
EP - 1132
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 7
ER -