Aberrant megakaryopoiesis in the myeloproliferative neoplasms.

骨髓增生性肿瘤中异常的巨核细胞生成。

基本信息

批准号：
9922491
负责人：
John D Crispino
金额：
$ 7.28万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922491
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 STK6 gene Signal Transduction Specimen Spleen Splenomegaly Therapeutic Transcript Transforming Growth Factor beta Translating Translations Work antitumor agent base cancer cell cytokine diphtheria toxin receptor improved outcome in vivo inhibitor/antagonist innovation insight leukemia mouse model mutant novel novel strategies novel therapeutics protein expression ribosome profiling selective expression small molecule transcription factor

项目摘要

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.

项目概要原发性骨髓纤维化（PMF）的特点是骨髓增生、髓外造血、骨骨髓纤维化、脾肿大和白血病进展。充满非典型巨核细胞，通过释放包括 TGF-β 在内的细胞因子导致纤维化。我们的首要假设是异常巨核细胞不仅是骨髓纤维化的关键驱动因素，还有原发性骨髓纤维化的其他表型，针对它们将改善这种疾病。第一个资助期，我们发现了诱导恶性细胞成熟和多倍化的小分子 PMF 小鼠模型以及原代人类患者标本中的巨核细胞基于该 NHLBI-。资助的研究，我们已经开始对其中一种巨核细胞多倍化剂进行一期试验， Alisertib，在 PMF 中在这次竞争更新中，我们将探讨 PMF 缺陷的分子性质。巨核细胞，并确定它们在疾病中的必要性和充分性。关键转录因子 GATA1 的表达在大多数人和小鼠中均受到抑制 PMF 巨核细胞并进一步表明这种缺陷是由于核糖体功能受损所致。提出了令人惊讶的结果，即 JAK2V617F 在巨核细胞中选择性表达足以引起在目标 1 中，我们将研究激活的 JAK/STAT 信号、GATA1 和之间的联系。在目标 2 中，我们将研究 JAK2 的巨核细胞表达如何影响核糖体的生长。还可以确定巨核细胞是否对该疾病至关重要。这项工作具有创新性。因为我们是第一个揭示巨核细胞疾病中核糖体存在缺陷的人 JAK2V617F 巨核细胞选择性表达不仅导致巨核细胞生成增强，而且还导致我们的研究具有重要意义，因为它将为细胞非自主方式的红细胞增多症提供新的线索。巨核细胞生物学和发病机制，可能有助于识别其他新的潜在疗法此外，我们的工作也与 Diamond Blackfan 贫血相关，因为 GATA1 突变说明了这一点。对于一部分病例，核糖体基因突变与 GATA1 之间似乎存在相关性最后，我们的研究将为支持代理的开发提供更多见解。在这种疾病中选择性地靶向巨核细胞。