Thrombopoietin signaling defect in polycythemia vera platelets

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...

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435 72, 435 721, 435 724, 435 725, G01N 3353, G01N 33567

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active

060279028

ABSTRACT:
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.

REFERENCES:
patent: 5656442 (1997-08-01), Ginsberg
Alison R. Moliterno et al. "Impaired Expression of the Thrombopoietin Receptor by Platelets from Patients with Polycythemia Vera" The New England Journal of Medicine 338:572-580 (Feb. 26, 1998).
Isabelle Vigon et al. "Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: Identification of a member of the hematopoietic growth factor receptor superfamily" Proc. Natl. Acad. Sci. USA vol. 89 pp. 5640-5644 Jun. 1992.
Vinecnt Mignotte et al. "Structure and Transcription of the Human c-mpl Gene (MPL)" Genomics 20, 5-12 (1994).
Y. Li et al. "Proto-oncogene c-mpl is involved in spontaneous megakaryocytopoiesis in myeloproliferative disorders." British Journal of Haematology 92 (1) 1996 60-66.
A. Moliterno et al.; "Thrombopoietin Fails to Stimulate Protein Tyrosine Phosphorylation in Polycythemia Vera Platelets"; Blood 88 (Suppl. 1); 1996; p640a, Abstract No. 2547.
A. Moliterno et al.; "Loss of Thrombopoietin Signal Transduction and it membrane receptor, Mpl, is Associated With Polycythemia Vera and Idiopathic Myelofibrosis".; Blood 90 (Suppl. 1); 1997; p346a, Abstract No. 1544.
Alison R. Moliterno et al.; "A Novel Thrombopoietin Signaling Defect In Polycythemia Vera Platelets", Stem Cells 1998; 16(suppl 2): pp. 185-192.

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