The role of AGK in thrombocytopoiesis and possible therapeutic strategies
The role of AGK in thrombocytopoiesis and possible therapeutic strategies
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AGK 在血小板生成中的作用和可能的治疗策略
DOI：
10.1182/blood.2019003851
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发表时间：
2020-07-02
期刊：
影响因子：
20.3
通讯作者：
Liu, Junling
中科院分区：
文献类型：
--
作者：
Jiang, Haojie;Yu, Zhuo;Liu, Junling
异常巨核细胞发育和血小板生成导致血小板减少症或血小板增多症，并增加出血或血栓形成的风险。酰基甘油激酶（Acylglycerol kinase，AGK）是一种线粒体膜激酶，催化β-磷脂酸和溶血磷脂酸的形成。AGK基因突变被认为是引起血小板减少综合征的主要原因，有报道称血小板减少综合征患者会出现血小板减少。在这项研究中，我们发现巨核细胞/血小板特异性AGK缺陷小鼠出现血小板减少症和脾肿大，主要是由于骨髓血小板生成效率低下和髓外造血过多引起的，而不是由循环血小板凋亡引起的。据报道，G126 E突变阻止了AGK的激酶活性。AGK G126 E突变不影响外周血小板计数或巨核细胞分化，表明AGK参与巨核细胞发育和血小板生物合成并不依赖于其激酶活性。Mpl/Janus激酶2（JAK 2）/信号转导子和转录激活子3（Stat 3）通路是调节巨核细胞发育的主要信号通路。我们的研究证实AGK可以与巨核细胞/血小板中的JAK 2结合。更有趣的是，我们发现JAK 2 V617 F突变显著增强了AGK与JAK 2的结合，并极大地促进了巨核细胞/血小板中响应血小板生成素的JAK 2/Stat 3信号传导。我们还发现JAK 2 JAK同源2结构域肽YGVCF 617 CGDENI增强AGK与JAK 2的结合，并且含有YGVCF 617 CGDENI序列的细胞可渗透肽加速前血小板形成。因此，我们的研究揭示了AGK在巨核细胞分化和血小板生物合成中的重要作用，并提示靶向AGK和JAK 2之间的相互作用可能是治疗血小板减少症或血小板增多症的新策略。
Abnormal megakaryocyte development and platelet production lead to thrombocytopenia or thrombocythemia and increase the risk of hemorrhage or thrombosis. Acylglycerol kinase (AGK) is a mitochondrial membrane kinase that catalyzes the formation of phos-phatidic acid and lysophosphatidic acid. Mutation of AGK has been described as the major cause of Sengers syndrome, and the patients with Sengers syndrome have been reported to exhibit thrombocytopenia. In this study, we found that megakaryocyte/platelet-specific AGK-deficient mice developed thrombocytopenia and splenomegaly, mainly caused by inefficient bone marrow thrombocytopoiesis and excessive extramedullary hematopoiesis, but not by apoptosis of circulating platelets. It has been reported that the G126E mutation arrests the kinase activity of AGK. The AGK G126E mutation did not affect peripheral platelet counts or megakaryocyte differentiation, suggesting that the involvement of AGK in megakaryocyte development and platelet biogenesis was not dependent on its kinase activity. The Mpl/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (Stat3) pathway is the major signaling pathway regulating megakaryocyte development. Our study confirmed that AGK can bind to JAK2 in megakaryocytes/platelets. More interestingly, we found that the JAK2 V617F mutation dramatically enhanced the binding of AGK to JAK2 and greatly facilitated JAK2/Stat3 signaling in megakaryocytes/platelets in response to thrombopoietin. We also found that the JAK2 JAK homology 2 domain peptide YGVCF 617 CGDENI enhanced the binding of AGK to JAK2 and that cell-permeable peptides containing YGVCF 617 CGDENI sequences accelerated proplatelet formation. Therefore, our study reveals critical roles of AGK in megakaryocyte dif-ferentiation and platelet biogenesis and suggests that targeting the interaction between AGK and JAK2 may be a novel strategy for the treatment of thrombocytopenia or thrombocythemia.