Mechanism of thrombosis in two myeloproliferative neoplasms (MPNs), polycythemia vera and essential thrombocythemia

两种骨髓增生性肿瘤（MPN）、真性红细胞增多症和原发性血小板增多症的血栓形成机制

• 批准号: 10699552
• 负责人: JOSEF T PRCHAL
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699552
• 关键词: Adult; Blood; Blood Cell Count; Blood Cells; Blood Platelets; Blood coagulation; Bone Marrow Cells; Cell Line; Cells; Cessation of life; Child; Clinical; Colony-forming units; Congenital Disorders; Data; Development; Disease; EDN1 gene; Endothelial Cells; Endothelium; Environment; Enzymes; Erythrocytes; Erythrocytoses; Gene Expression; Genes; Genetic Transcription; Goals; Hematocrit procedure; Hematopoietic; Hematopoietic Neoplasms; Hemorrhagic Thrombocythemia; Home; Hospitalization; Hypoxia; Incidence; Inflammation; Inflammatory; Iron; JAK1 gene; JAK2 gene; Laboratory Finding; Legal patent; Leukocytes; MPL gene; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Multivariate Analysis; Mutate; Mutation; Myeloproliferative disease; Patients; Persons; Physicians; Play; Polycythemia; Polycythemia Vera; Prevention; Procollagen-Proline Dioxygenase; Protein S; Publishing; Recording of previous events; Registries; Regulation; Research; Risk; Role; Signal Transduction; Somatic Mutation; Source; Testing; Thromboplastin; Thrombosis; Transcript; Up-Regulation; VHL mutation; Venous Thrombosis; Venous blood sampling; White Blood Cell Count procedure; Work; Zinc Fingers; calreticulin; cancer type; chronic leukemia; cofactor; follow-up; granulocyte; hypoxia inducible factor 1; inhibitor; interest; iron deficiency; monocyte; mortality; neutrophil; new therapeutic target; novel; premature; prevent; prospective; stem cells; thrombotic; transcription factor

Project Summary/Abstract Arterial and venous thromboses are the major causes of morbidity and mortality in in two myeloproliferative neoplasms (MPNs): polycythemia vera (PV) and essential thrombocythemia (ET), associated with JAK2, and in ET in addition to JAK2 also calreticulin (CALR), and infrequently thrombopoietin receptor (cMPL) somatic mutations. However, the molecular mechanism of thrombosis is largely unknown. In multivariate analyses, the leukocyte count independently correlates with their risk of thromboses. Our published work demonstrates that the hypoxia inducible transcription factors (HIF-1 and HIF-2), which are upregulated in both granulocytes and platelets in PV and ET, promote the transcription of prothrombotic and proinflammatory genes. Leukocytes are the only source of tissue factor (TF) in the blood, and we also showed that PV neutrophils constitutively express TF activity. Transcripts of Krüppel-like Factor 2 (KLF2) - a zinc finger transcription factor, are down regulated in granulocytes and platelets from PV and ET patients and correlate inversely with the transcripts of prothrombotic genes, suggesting that KLF2 might be a suppressor of thrombotic gene expression in these conditions. In Chuvash erythrocytosis/polycythemia (CE) - a congenital disorder associated with increased HIF-1 and HIF-2 due to a hypomorphic R200W mutation of the Von Hippel- Lindau (VHL) gene, the incidence of thrombosis is higher than in PV and phlebotomy did not prevent thrombosis but instead appeared to have facilitated it. Repeated phlebotomies induced iron deficiency (ID) which further increased the level of HIF-1 and HIF-2 by inhibiting the negative HIFs regulator prolyl hydroxylase domain 2 (PHD2) enzyme, which requires iron as a co-factor. Therefore, we hypothesize that the up-regulation of HIF signaling in ET and PV granulocytes and platelets, perhaps with an additional contribution of augmented inflammation, plays a central role in the development of thrombosis. In order to achieve our objective, we propose to follow these specific aims (SA): SA 1a. Determine whether the correction of ID decreases HIF signaling and ameliorates the thrombotic milieu in PV and ET. SA 1b. Determine the effect of HIFs in PV and ET thrombosis using inhibitors of HIF-1, HIF2 and JAKs. SA 2. Extend our observations from mRNA transcripts of HIF-regulated, prothrombotic and antithrombotic genes and inflammatory genes to the activity of TF in all blood lineages. SA 3. Determine the role of KLF2 in increasing the risk of thrombosis in PV and ET and its regulation and elucidate in more detail the interaction of KLF2 and HIFs. We submit that proving our hypothesis will uncover novel mechanisms of thrombosis in PV and ET and open new therapeutic targets for prevention of thrombosis in PV and ET.

项目摘要/摘要 动脉和静脉血栓形成是两种发病率和死亡率的主要原因 骨髓增生性肿瘤（MPN）：多余细胞增多症（PV）和必需血小板血症（ET），，，， 与JAK2和ET相关，除JAK2还钙网蛋白（CALR），并且很少 血小板素受体（CMPL）体细胞突变。但是， 血栓形成在很大程度上未知。在多元分析中，白细胞计数独立关联 有血栓形成的风险。我们发表的工作表明缺氧诱导 转录因子（HIF-1和HIF-2），在粒细胞和血小板中都上调 PV和ET，促进促血栓形成和促炎基因的转录。白细胞是 血液中组织因子（TF）的唯一来源，我们还显示了PV中性粒细胞 表达TF活动。 Krüppel样因子2（KLF2）的成绩单 - 锌指转录因子是 从PV和ET患者的粒细胞和血小板中调节，并与 促血栓性基因的转录本，表明KLF2可能是血栓形成基因的抑制剂 在这些条件下的表达。在Chuvash红细胞增多症/多性炎症（CE）中 - 先天性疾病 由于von Hippel- lindau（VHL）基因，血栓形成的事件高于PV，而静脉切开术并不能阻止 血栓形成，但似乎已经准备好了。反复的静脉诱导铁缺乏症 （ID）通过抑制负HIFS调节器进一步提高HIF-1和HIF-2的水平 丙酰羟化酶结构域2（PHD2）酶，需要铁作为副因子。因此，我们 假设ET和PV粒细胞和血小板中HIF信号的上调，也许 还具有增强感染的额外贡献，在发展中起着核心作用 血栓形成。为了实现我们的目标，我们建议遵循这些特定目标（SA）： SA 1A。确定ID校正是否会降低HIF信号传导并改善血栓形成 Milieu在PV和ET中。 SA 1B。使用HIF-1，HIF2和JAKS的抑制剂确定HIF在PV和ET血栓形成中的影响。 SA 2。从HIF调节，血栓形成和 抗血栓形成基因和炎症基因对TF在所有血统中的活性。 SA 3。确定KLF2在增加PV和ET中血栓形成风险及其调节中的作用 并更详细地阐明KLF2和HIF的相互作用。 我们认为证明我们的假设将发现PV和ET中血栓形成的新型机制 并开放新的治疗靶标，以预防PV和ET中的血栓形成。