Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia
Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia
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DOI：
10.1182/bloodadvances.2019001379
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发表时间：
2020-03-24
期刊：
影响因子：
7.5
通讯作者：
Prchal, Josef T.
中科院分区：
文献类型：
--
作者：
Gangaraju, Radhika;Song, Jihyun;Prchal, Josef T.
血栓形成是真性红细胞增多症（PV）和原发性血小板增多症（ET）发病和死亡的主要原因。这些疾病中血栓形成的病理生理学尚不清楚，我们假设血栓形成，炎症和缺氧诱导因子（HIF）调节基因的上调可能在其中发挥作用。我们在PV患者的粒细胞和血小板中进行了无偏RNA测序，发现了几个血栓形成，炎症和HIF调节基因的差异表达。这些基因中的许多基因的表达与JAK 2表达和JAK 2（V617 F）等位基因负荷正相关。然后，我们通过定量聚合酶链反应分析大量PV和ET粒细胞和血小板（58例患者）和28例对照中选定的基因转录物来验证这些发现，并比较了有和无血栓形成患者的这些发现。该研究包括29名女性和29名男性;其中28名有血栓形成病史。我们发现，与对照组相比，PV或ET患者的几个选定的基因转录上调。在粒细胞中，F3、SELP、VEGFA和SLC 2A 1的表达水平在有血栓形成史的患者中显著高于无血栓形成史的患者。有血栓形成史的患者血小板中IL 1 RAP的表达显著高于无血栓形成的患者（P <0.05）。我们的研究证实了存在血栓炎性状态和增强的HIF活性在PV和ET及其在血栓形成中的作用。这些数据可能为PV和ET的靶向治疗提供背景。
Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)-regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2(V617F) allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thromboinflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.