Increased cell surface expression of C-terminal truncated erythropoietin receptors in polycythemia.
ABSTRACT Primary familial and congenital polycythemia (PFCP) is a disorder characterized by an increased number of erythrocytes despite normal blood oxygen pressure and a normal serum erythropoietin (EPO) level. Recent studies revealed that erythroid progenitor cells from certain individuals with PFCP express various forms of EPO receptor (EPOR) truncated at the terminal carboxyl site (EPOR-TTC(PFCP)). EPOR-TTC(PFCP) can transmit EPO-mediated proliferative signals more efficiently than can full-length EPOR (EPOR-F), at least partly because of defective recruitment of SHP-1 phosphatase to these receptors. In agreement with previous studies, Ba/F3 transfectants expressing EPOR-TTC(PFCP) showed higher proliferative responses to EPO. In those transfectants, we found that EPOR-TTC(PFCP) was expressed more abundantly on the cell surface than was EPOR-F. This tendency was confirmed by a transient-expression experiment using COS7 cells. Since expression levels of EPOR protein were not significantly different among these transfectants, differences in cell surface expression were likely dependent on post-translational mechanism(s). In addition to defective recruitment of SHP-1 to EPOR-TTC(PFCP), more efficient transport and expression on the cell surface appear to serve as mechanisms responsible for increased EPO-responsiveness of erythroid progenitor cells in PFCP.
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ABSTRACT: The molecular pathogenesis of ET and PV is unknown, although the relatively indolent clinical course observed in most patients suggests that the defect may be subtle and difficult to establish. Clonality analysis using X-chromosome inactivation patterns in females on purified CD34+ cells have confirmed that a defect is present in the hematopoietic stem cell. However, at least in ET, a significant proportion of patients have polyclonal hemopoiesis, and this presumably reflects the heterogeneous nature of the disorder(s). Attention has focussed on the potential disruption of the physiological regulators EPO and TPO and their respective receptors. In familial disorders, pathological mutations have been identified in some, but by no means all, cases: EPO receptor mutations in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in CAMT. Equivalent ligand or receptor mutations have not been detected in ET or PV patients. However, there is evidence to suggest that c-mpl expression may be dysregulated, with low or absent c-mpl mRNA or protein reported in ET and/or PV patients. At present it is not clear whether this is the cause or consequence of the paradoxically normal/increased TPO levels found with both primary and secondary thrombocytosis. In vitro culture analysis has demonstrated both cytokine independence and hyper-sensitivity as a generalised feature of progenitor cells from many patients, but differences exist depending on the assays used and there is little understanding of the mechanism(s) underlying these responses. Two genes have recently been identified with increased mRNA expression in PV granulocytes: PRV-1, a novel cell surface receptor closely related to the uPAR/Ly6/CD59/snake toxin family of proteins, and NFI-B, a member of the nuclear factor I family which may be associated with TGF-beta resistance. Investigation of their regulation and biological effects may assist in determining the pathobiology of these elusive disorders.International Journal of Hematology 09/2002; 76 Suppl 2:305-10. · 1.27 Impact Factor