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.

项目概要/摘要 动脉和静脉血栓是两种疾病发病和死亡的主要原因 骨髓增生性肿瘤（MPN）：真性红细胞增多症（PV）和原发性血小板增多症（ET）， 与 JAK2 相关，在 ET 中，除了 JAK2 之外，还与钙网蛋白 (CALR) 相关，并且很少见 然而，血小板生成素受体（cMPL）体细胞突变的分子机制。 在多变量分析中，血栓形成很大程度上是未知的。 我们发表的研究表明，缺氧会导致血栓形成。 转录因子（HIF-1 和 HIF-2），在粒细胞和血小板中均上调 PV 和 ET 促进白细胞促血栓和促炎基因的转录。 血液中组织因子（TF）的唯一来源，我们还表明PV中性粒细胞组成型 表达 Krüppel 样因子 2 (KLF2)（一种锌指转录因子）的转录物。 PV 和 ET 患者的粒细胞和血小板中下调，并与 促血栓基因的转录本，表明 KLF2 可能是血栓基因的抑制因子 在楚瓦什红细胞增多症/红细胞增多症 (CE) 中表达 - 一种先天性疾病。 由于 Von Hippel 的亚等位性 R200W 突变，与 HIF-1 和 HIF-2 增加相关 Lindau (VHL) 基因，血栓形成的发生率高于 PV，且放血不能预防 血栓形成，但反复放血似乎促进了铁缺乏。 (ID) 通过抑制负 HIF 调节剂进一步增加 HIF-1 和 HIF-2 的水平 脯氨酰羟化酶结构域 2 (PHD2) 酶，需要铁作为辅助因子，因此，我们。 ET 和 PV 粒细胞和血小板中 HIF 信号的上调 加上增强炎症的额外贡献，在疾病的发展中起着核心作用 为了实现我们的目标，我们建议遵循以下具体目标 (SA)： SA 1a. 确定 ID 的校正是否会减少 HIF 信号传导并改善血栓形成 PV 和 ET 环境。 SA 1b. 使用 HIF-1、HIF2 和 JAK 抑制剂确定 HIF 对 PV 和 ET 血栓形成的影响。 SA 2. 扩展我们对 HIF 调节的、促血栓形成和 抗血栓基因和炎症基因对所有血统中 TF 的活性都有影响。 SA 3.确定KLF2在增加PV和ET血栓形成风险中的作用及其调节 并更详细地阐明 KLF2 和 HIF 的相互作用。 我们认为，证明我们的假设将揭示 PV 和 ET 血栓形成的新机制 并为预防PV和ET中的血栓形成开辟新的治疗靶点。