Impaired TPO-mediated platelet protein tyrosine phosphorylation was consistently observed in patients with polycythemia vera (PV) as well as those with idiopathic myelofibrosis (IMF), in contrast to patients with essential thrombocytosis, chronic myelogenous leukemia, secondary erythrocytosis, iron deficiency anemia, hemochromatosis or normal volunteers. Moreover, the platelet TPO receptor, Mpl, was not detectable by immunoblotting with an antibody to the extracellular domain, by chemical crosslinking of TPO to the surface of platelets, or by flow cytometry using an antibody to the extracellular domain, in 34 of 34 PV patients and also in 13 of 14 IMF patients. Impaired TPO-induced protein tyrosine phosphorylation in PV and IMF platelets was uniformly associated with markedly reduced or absent expression of the extracellular domain of Mpl. Thus the reduced detectablility of Mpl by these methods can be used a marker of PV and IMF. The abnormality appears to distinguish PV from other forms of erythrocytosis and may be involved in the platelet function defect associated with PV.

The Johns Hopkins University

Antibodies to the cytoplasmic domain of the thrombopoietin receptor

Johns Hopkins University

Thrombopoietin signaling defect in polycythemia vera platelets

Methods to assay a thrombopoietin signaling defect in polycythemia vera platelets

Human erythroid p55, an abundantly palmitoylated erythrocyte membrane protein, has been identified, cloned and sequenced. p55 appears to be ubiquitously expressed in human tissues and contains both an SH3 motif and an enzymatically active guanylate kinase domain. The presence of the SH3 motif indicates a possible role in the suppression of tyrosine kinase activity and the guanylate kinase domain may play a role in signal transduction and tissue proliferation by modulating guanine nucleotide levels. Localized to the Xq24-qter region of the X chromosome, abnormalities in p55 appear in patients suffering from hemolytic anemia and Dyskeratosis congenita. With the identification and sequencing of p55, nucleic acid probes and anti-p55 antibodies can be used in a variety of hybridization and immunological assays to screen for and detect p55 defects. Conventional and gene techniques can also be developed to treat p55 deficiencies and abnormalities.

anemia/tyrosine

Antibodies to the cytoplasmic domain of the thrombopoietin receptor

Thrombopoietin signaling defect in polycythemia vera platelets

Methods to assay a thrombopoietin signaling defect in polycythemia vera platelets

Human erythroid p55 nucleic acids

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