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 动脉和静脉血栓是两年中发病率和死亡率的主要原因 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，并且在ET中除JAK2外还包括钙网蛋白(CALR)，而且很少见 血小板生成素受体(CMPL)体细胞突变。然而，其分子机制 血栓形成在很大程度上是未知的。在多变量分析中，白细胞计数独立地与 他们有患血栓的风险。我们发表的研究表明，低氧可诱导 转录因子(HIF-1和HIF-2)，它们在粒细胞和血小板中均上调 PV和ET促进血栓前基因和促炎基因的转录。白细胞是 是血液中组织因子(TF)的唯一来源，我们还发现PV中性粒细胞 表达转铁蛋白活性。锌指转录因子Krf2的转录本如下 PV和ET患者外周血中粒细胞和血小板表达下调，并与 血栓前基因的转录，提示KLF2可能是血栓基因的抑制因子 在这些条件下的表达。丘瓦什的红细胞增多症/红细胞增多症(CE)--一种先天性疾病 与由于冯·希佩尔R200W亚型突变导致的HIF-1和HIF-2增加有关- Lindau(VHL)基因，血栓的发生率高于PV，而放血并不能预防 血栓形成，但似乎反而促进了它的发生。反复抽血导致铁缺乏 (ID)通过抑制负HIFs调节因子进一步增加HIF-1和HIF-2的水平 脯氨酸羟基酶结构域2(PHD2)，需要铁作为辅助因子。因此，我们 假设ET和PV粒细胞和血小板中HIF信号的上调，可能 此外，由于炎症的加剧，它在 血栓形成。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的纠正是否减少了HIF信号，并改善了血栓形成 在PV和ET中的环境。 Sa 1b.使用HIF-1、HIF2和JAKs的抑制剂确定HIF在PV和ET血栓形成中的作用。 SA 2.扩展我们从HIF调节的、血栓前的和 抗血栓基因和炎症基因对所有血系中转铁蛋白活性的影响。 确定KLF2在增加PV和ET血栓形成风险中的作用及其调节 并更详细地阐明了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中血栓形成的新机制 为预防静脉曲张和ET血栓形成开辟新的治疗靶点。