The thrombopoietin receptor: revisiting the master regulator of platelet production.
The thrombopoietin receptor: revisiting the master regulator of platelet production.
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DOI：
10.1080/09537104.2021.1925102
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发表时间：
2021-08-18
期刊：
影响因子：
3.3
通讯作者：
Tucker JA
中科院分区：
文献类型：
--
作者：
Hitchcock IS;Hafer M;Sangkhae V;Tucker JA
血小板生成素（TPO）及其受体MPL是血小板生成的主要调节因子，对造血干细胞（HSC）的维持至关重要。自1994年首次克隆TPO以来，TPO和MPL的生理和病理作用已得到充分表征，最终于2008年批准第一种MPL激动剂用于治疗慢性免疫性血小板减少症。TPO-MPL信号轴的失调有助于血液系统疾病的发病机制：表达或功能下降导致严重的血小板减少症进展为骨髓衰竭，而MPL信号传导的过度激活（无论是通过受体突变还是相关的Janus激酶2（JAK 2）），导致病理性骨髓增生。尽管其重要性，但直到最近才解决了关于TPO结合激活MPL的机制的长期争论。本次审查将涵盖TPO和MPL的结构和功能的关键方面及其在受体激活的重要性，讨论这些是如何改变血液疾病，并考虑如何更好地了解可能导致更好的目标和更有效的治疗方法的发展。
Thrombopoietin (TPO) and its receptor, MPL, are the primary regulators of platelet production and critical for hematopoietic stem cell (HSC) maintenance. Since TPO was first cloned in 1994, the physiological and pathological roles of TPO and MPL have been well characterized, culminating in the first MPL agonists being approved for the treatment of chronic immune thrombocytopenia in 2008. Dysregulation of the TPO-MPL signaling axis contributes to the pathogenesis of hematological disorders: decreased expression or function results in severe thrombocytopenia progressing to bone marrow failure, while hyperactivation of MPL signaling, either by mutations in the receptor or associated Janus kinase 2 (JAK2), results in pathological myeloproliferation. Despite its importance, it was only recently that the long-running debate over the mechanism by which TPO binding activates MPL has been resolved. This review will cover key aspects of TPO and MPL structure and function and their importance in receptor activation, discuss how these are altered in hematological disorders and consider how a greater understanding could lead to the development of better-targeted and more efficacious therapies.
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