Aberrant megakaryopoiesis in the myleoproliferative neoplasms

项目总结 原发性骨髓纤维化(PMF)的特征是骨髓增殖、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 充满了非典型的巨核细胞，通过释放包括转化生长因子-β在内的细胞因子而导致纤维化。 我们的主要假设是，异常巨核细胞不仅是骨髓纤维化的关键驱动因素， 而且还有其他表型的原发性骨髓纤维化，以它们为靶点将会改善这种疾病。在 在第一个资助期，我们发现了诱导肿瘤细胞成熟和多倍化的小分子。 PMF小鼠模型和人类原代患者标本中的巨核细胞。基于这个NHLBI- 在资助的研究中，我们已经开启了这些巨核细胞多倍体制剂之一的第一阶段试验， Alisertib，以PMF表示。在这一竞争更新中，我们将探索PMF缺陷的分子本质 巨核细胞，并确定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GATA1在大多数人和小鼠中的表达都受到抑制 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。我们也 提出了令人惊讶的结果：JAK2V617F在巨核细胞中的选择性表达足以导致 活体内红细胞增多症。在目标1中，我们将研究激活的JAK/STAT信号、GATA1和 核糖体功能。在目标2中，我们将研究JAK2的巨核细胞表达如何影响细胞的生长 并确定巨核细胞是否在疾病中起重要作用。这项工作具有创新性 因为我们是第一个发现巨核细胞疾病中存在核糖体缺陷的人，而且 JAK2V617F的巨核细胞选择性表达不仅能增强巨核细胞的生成，而且还能 细胞非自主性的红细胞增多症。我们的研究具有重要意义，因为它将为 巨核细胞生物学和发病机制，可能有助于确定其他新的潜在治疗方法 对于MPN来说。此外，我们的工作也与钻石黑粉贫血有关，因为GATA1突变解释了 对于一部分病例，核糖体基因突变和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来支持以下代理的开发 在这种疾病中选择性地靶向巨核细胞。

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.