A novel thrombopoietin signaling defect in polycythemia vera platelets.
A novel thrombopoietin signaling defect in polycythemia vera platelets.
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真性红细胞增多症血小板中一种新型血小板生成素信号缺陷。
DOI：
10.1002/stem.5530160721
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Spivak,JL
中科院分区：
文献类型：
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作者：
Moliterno,AR;Siebel,KE;Sun,AY;Hankins,WD;Spivak,JL
真性红细胞增多症（PV）是一种涉及多能造血祖细胞的疾病，其发病机制尚不清楚。血小板生成素（TPO）是一种新发现的造血生长因子，它调节多能造血祖细胞和血小板的生成。为了评估TPO介导的信号转导异常可能参与PV发病机制的可能性，我们使用血小板作为替代模型系统检测了TPO诱导的蛋白酪氨酸磷酸化。从PV患者以及其他慢性骨髓增生性疾病患者和对照受试者的血液中分离血小板。TPO介导的血小板蛋白酪氨酸磷酸化受损是PV患者以及特发性骨髓纤维化（IMF）患者的一致观察结果，与原发性血小板增多症、慢性髓细胞性白血病、继发性红细胞增多症、缺铁性贫血、血色素沉着症或正常志愿者患者相反。凝血酶介导的血小板蛋白酪氨酸磷酸化在PV血小板中是完整的，适当的酪氨酸激酶及其同源底物的表达也是如此。然而，血小板TPO受体，Mpl的表达，免疫印迹，化学交联或流式细胞术测定显着减少或不存在34 34 PV患者和13 14 IMF患者。PV和IMF血小板中TPO诱导的蛋白酪氨酸磷酸化受损与Mpl表达显著降低或缺失一致相关。我们的结论是减少表达的Mpl是一个表型特征的血小板从PV和IMF患者。该异常似乎可以将PV与其他形式的红细胞增多症区分开来，并可能与PV相关的血小板功能缺陷有关。
The pathogenesis of polycythemia vera (PV), a disease involving a multipotent hematopoietic progenitor cell, is unknown. Thrombopoietin (TPO) is a newly characterized hematopoietic growth factor which regulates the production of multipotent hematopoietic progenitor cells as well as platelets. To evaluate the possibility that an abnormality in TPO‐mediated signal transduction might be involved in the pathogenesis of PV, we examined TPO‐induced protein tyrosine phosphorylation using platelets as a surrogate model system. Platelets were isolated from the blood of patients with PV as well as from patients with other chronic myeloproliferative disorders and control subjects. Impaired TPO‐mediated platelet protein tyrosine phosphorylation was a consistent observation in patients with 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. Thrombin‐mediated platelet protein tyrosine phosphorylation was intact in PV platelets as was expression of the appropriate tyrosine kinases and their cognate substrates. However, expression of the platelet TPO receptor, Mpl, as determined by immunoblotting, chemical crosslinking or flow cytometry was markedly reduced or absent 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 Mpl. We conclude that reduced expression of Mpl is a phenotypic characteristic of platelets from patients with 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.