Aberrant megakaryopoiesis in the myeloproliferative neoplasms.

骨髓增生性肿瘤中异常的巨核细胞生成。

• 批准号: 9922938
• 负责人: John D Crispino
• 金额: $ 41.89万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922938
• 关键词: Abnormal megakaryocyte; Animal Model; Biology; Blood Platelet Disorders; Bone Marrow; Cells; Clinical; Collaborations; Data; Defect; Development; Diamond-Blackfan anemia; Disease; Down-Regulation; Extramedullary Hematopoiesis; Fibrosis; Funding; Future; GATA1 gene; Gene Expression; Gene Mutation; Genes; Goals; Growth; Hematopoiesis; Hematopoietic stem cells; Human; Impairment; JAK2 gene; Lead; Light; Link; Malignant - descriptor; Mediating; Megakaryocytes; Megakaryocytopoieses; Methods; Molecular Probes; Mus; Mutation; Myelofibrosis; Myelogenous; Myeloproliferation; Myeloproliferative disease; National Heart, Lung, and Blood Institute; Nature; Non-Malignant; Pathogenesis; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Polycythemia; Primary Myelofibrosis; RNA Processing; Reporting; Research; Ribosomal RNA; Ribosomes; Role; STAT protein; Signal Transduction; Specimen; Spleen; Splenomegaly; Therapeutic; Transcript; Transforming Growth Factor beta; Translating; Translations; Work; antitumor agent; aurora kinase A; base; cancer cell; cytokine; diphtheria toxin receptor; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; leukemia; mouse model; mutant; novel; novel strategies; novel therapeutics; phase I trial; protein expression; ribosome profiling; selective expression; small molecule; transcription factor

PROJECT SUMMARY Primary myelofibrosis (PMF) is characterized by myeloproliferation, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients are full of atypical megakaryocytes that contribute to fibrosis through the release of cytokines including TGF-β. Our overarching hypothesis is that abnormal megakaryocytes are key drivers of not only bone marrow fibrosis, but also other phenotypes of primary myelofibrosis, and that targeting them will ameliorate the disease. In the first funding period, we identified small molecules that induce maturation and polyploidization of malignant megakaryocytes in mouse models of PMF as well as primary human patient specimens. Based on this NHLBI- funded research, we have opened a Phase 1 trial of one of these megakaryocyte polyploidization agents, Alisertib, in PMF. In this competing renewal, we will probe the molecular nature of the defects in PMF megakaryocytes, and also determine their necessity and sufficiency in the disease. Our preliminary data show that expression of the key transcription factor GATA1 is suppressed in the majority of both human and mouse PMF megakaryocytes and further suggest that this deficiency is due to impaired ribosome function. We also present the surprising result that expression of JAK2V617F selectively in megakaryocytes is sufficient to cause polycythemia in vivo. In Aim 1, we will investigate the link between activated JAK/STAT signaling, GATA1, and ribosome function. In Aim 2 we will study how megakaryocyte expression of JAK2 influences the growth of other cells and also determine whether megakaryocytes are essential for the disease. This work is innovative in that we are the first to reveal that there is defect in ribosomes in a megakaryocytic disorder and that megakaryocyte-selective expression of JAK2V617F leads not only to enhanced megakaryopoiesis, but also to polycythemia in a cell non-autonomous manner. Our research is significant in that it will shed new light on megakaryocyte biology and pathogenesis and may aid in the identification of additional new potential therapies for the MPNs. In addition, our work is also relevant to Diamond Blackfan Anemia, as GATA1 mutations account for a subset of cases and there appears to be a relationship between ribosomal gene mutations and GATA1 translation. Finally, our research will provide additional insights to support the development of agents that selectively target megakaryocytes in this disease.

项目摘要 原发性骨髓纤维化（PMF）的特征是骨髓增生，外尿外造血，骨头 骨髓纤维化，脾肿大和白血病进展。此外，患者的骨髓和脾脏 充满了非典型的巨核细胞，通过释放包括TGF-β在内的细胞因子释放纤维化。 我们的总体假设是，异常的巨核细胞不仅是骨髓纤维化的关键驱动因素，而且是 但是，原发性骨髓纤维化的其他表型以及靶向它们的表型将改善疾病。在 首先，我们确定了影响恶性成熟和多倍化的小分子 PMF小鼠模型以及原发性人类患者标本中的巨核细胞。基于此NHLBI- 资助的研究，我们已经开设了这些巨核细胞多倍体化剂之一的1期试验，即 Alisertib，在PMF中。在这种竞争的更新中，我们将探测PMF缺陷的分子性质 巨核细胞，还确定它们在疾病中的必要和充分性。我们的初步数据显示 在大多数人和小鼠中，关键转录因子GATA1的表达被抑制 PMF巨核细胞并进一步表明这种缺陷是核糖体功能受损引起的。我们也是 提出令人惊讶的结果，即在巨核细胞中选择性地表达JAK2V617F足以引起 体内多余炎症。在AIM 1中，我们将研究激活的JAK/Stat信号，GATA1和 核糖体功能。在AIM 2中，我们将研究巨核细胞的JAK2表达如何影响 其他细胞，还确定巨核细胞是否对疾病至关重要。这项工作是创新的 因为我们是第一个揭示巨核细胞疾病中核糖体缺陷的人，并且 JAK2V617F的巨核细胞选择性表达不仅可以增强巨型杂质，而且导致 细胞非自治方式的多性炎症。我们的研究很重要，因为它将为 巨核细胞生物学和发病机理，并可能有助于识别其他新的潜在疗法 对于MPN。此外，我们的工作也与钻石黑芬贫血有关，因为GATA1突变帐户 对于一部分病例，核糖体基因突变与GATA1之间似乎存在关系 翻译。最后，我们的研究将提供更多的见解，以支持代理的发展 有选择地靶向这种疾病的巨核细胞。