Aberrant megakaryopoiesis in the myleoproliferative neoplasms

项目摘要 原发性骨髓纤维化（PMF）的特征是骨髓增生、髓外造血、骨 骨髓纤维化、脾肿大和白血病进展。此外，患者的骨髓和脾脏 充满非典型巨核细胞，其通过释放包括TGF-β的细胞因子而促成纤维化。 我们的总体假设是，异常巨核细胞不仅是骨髓纤维化的关键驱动因素， 而且还包括原发性骨髓纤维化的其他表型，靶向它们将改善疾病。在 在第一个资助期，我们鉴定了诱导恶性肿瘤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。基于这个NHLBI- 资助的研究，我们已经开始了这些巨核细胞多倍化剂之一的1期试验， Alisertib，PMF。在这个竞争性的更新中，我们将探索PMF中缺陷的分子本质 巨核细胞，也决定了它们在疾病中的必要性和充分性。我们的初步数据显示 关键转录因子GATA 1的表达在大多数人和小鼠中被抑制， PMF巨核细胞，并进一步表明，这种缺陷是由于受损的核糖体功能。我们也 提出了令人惊讶的结果，即JAK 2 V617 F在巨核细胞中的选择性表达足以引起 体内红细胞增多症。在目标1中，我们将研究激活的JAK/STAT信号传导，GATA 1， 核糖体功能在目标2中，我们将研究巨核细胞JAK 2的表达如何影响巨核细胞的生长。 其他细胞，也决定是否巨核细胞是必不可少的疾病。这项工作是创新的 因为我们是第一个揭示在巨核细胞疾病中核糖体存在缺陷， JAK 2 V617 F的巨核细胞选择性表达不仅导致增强的巨核细胞生成，而且还导致 红细胞增多症以细胞非自主的方式。我们的研究意义重大，因为它将为我们提供新的视角， 巨核细胞生物学和发病机制，并可能有助于确定其他新的潜在治疗方法 对于MPN。此外，我们的工作也与Diamond Blackfan贫血有关，因为GATA 1突变解释了 对于一个病例子集，核糖体基因突变和GATA 1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，以支持开发代理， 选择性靶向巨核细胞

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.