Role of JAK2V617F in the Pathogenesis of Myeloproliferative Disorders.

JAK2V617F 在骨髓增殖性疾病发病机制中的作用。

• 批准号: 8241995
• 负责人: Golam Mohi
• 金额: $ 38.86万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241995
• 关键词: Address; Alleles; Animal Model; Biochemical; Bone Marrow Transplantation; Cell Line; Cell Lineage; Cell Proliferation; Cells; Cessation of life; Chromosomal translocation; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Clinical; Dysmyelopoietic Syndromes; Family; Gene Dosage; Genetic; Goals; Health; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hemorrhagic Thrombocythemia; Janus kinase 2; Knock-in Mouse; Lead; Mediating; Molecular; Mus; Mutation; Myelogenous; Myeloproliferative disease; PDGFRA gene; Pathogenesis; Pathology; Patients; Phenotype; Philadelphia Chromosome; Platelet-Derived Growth Factor beta Receptor; Point Mutation; Polycythemia Vera; Primary Myelofibrosis; Process; Protein Tyrosine Kinase; Public Health; Research; Role; Signal Pathway; Signal Transduction; System; Testing; Transgenic Model; base; bcr-abl Fusion Proteins; disease phenotype; insight; leukemia; new therapeutic target; novel; novel therapeutic intervention; progenitor; promoter; selective expression; transcription factor

DESCRIPTION (provided by applicant): Myeloproliferative disorders (MPDs) are clonal hematologic malignancies characterized by overproduction of one or more myeloid lineage cells. Chromosomal translocations or mutations in protein tyrosine kinases are frequently observed in MPDs. For example, BCR-ABL, the product of Philadelphia chromosome translocation, is associated with chronic myeloid leukemia (CML). Fusion of the Ets family transcription factor TEL to platelet-derived growth factor receptor beta (PDGFR2) results in chronic myelomonocytic leukemia (CMML). A somatic point mutation (V617F) in the Janus Kinase 2 (JAK2) has been found in majority of patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Murine bone marrow transplant and transgenic models of JAK2V617F demonstrate the importance of JAK2 activation in the pathogenesis of MPDs. However, it remains elusive how a single JAK2V617F allele gives rise to three different MPDs- PV, ET and PMF with distinct clinical features. Moreover, the signaling requirement and the precise mechanism for transformation/MPD by JAK2V617F remain largely unknown. In Preliminary Studies, we have developed a novel inducible JAK2V617F knock-in mouse. We will use this inducible knock-in mouse to define the role of JAK2V617F in MPDs. We will examine the effects of JAK2V617F gene dosage (heterozygosity versus homozygosity) on MPD phenotype. We will test if transformation of distinct progenitors results in distinct MPD. We will also assess the potential contribution of genetic background/host modifier on MPD pathogenesis. Using a genetic approach, we will also identify the signaling requirement for JAK2V617F-mediated transformation/MPD. These studies should lead to a better understanding of the role of JAK2V617F in the molecular pathogenesis of myeloproliferative disorders. Moreover, our JAK2V617F knock-in mice will provide a unique and reproducible animal model to test novel therapeutic approaches for JAK2V617F-associated pathologies. PUBLIC HEALTH RELEVANCE: This proposal aims to investigate the role of JAK2V617F mutation in the molecular pathogenesis of MPDs using a novel inducible JAK2V617F knock-in mouse. The proposed studies will provide important new insights into the molecular mechanism of MPDs. The results of these studies may identify new therapeutic targets for MPDs. Moreover, our inducible JAK2V617F knock-in mouse will provide a unique and reproducible animal model to test novel therapies for JAK2V617F-associated MPDs.

描述(申请人提供)：骨髓增生性疾病(MPD)是以一个或多个髓系细胞过度生产为特征的克隆性血液系统恶性肿瘤。染色体易位或蛋白酪氨酸激酶突变常见于MPD。例如，费城染色体易位的产物bcr-abl与慢性粒细胞白血病(CML)有关。ETS家族转录因子TEL与血小板衍生生长因子受体β(PDGFR2)的融合导致慢性粒单核细胞白血病(CMML)。在大多数真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)患者中发现Janus Kinase 2(JAK2)的体细胞点突变(V617F)。小鼠骨髓移植和JAK2V617F转基因模型证实了JAK2激活在MPDS发病机制中的重要性。然而，单个JAK2V617F等位基因如何导致三种不同的MPD-PV、ET和PMF-具有不同的临床特征仍然难以捉摸。此外，JAK2V617F对转换/MPD的信号要求和确切机制在很大程度上仍不清楚。在初步研究中，我们开发了一种新型的可诱导JAK2V617F敲入小鼠。我们将使用这种可诱导的敲入小鼠来确定JAK2V617F在MPDS中的作用。我们将研究JAK2V617F基因剂量(杂合性与纯合性)对MPD表型的影响。我们将测试不同祖先的转换是否会导致不同的MPD。我们还将评估遗传背景/宿主调节因子在MPD发病机制中的潜在作用。使用遗传方法，我们还将确定JAK2V617F介导的转化/MPD的信号需求。这些研究将有助于更好地理解JAK2V617F在骨髓增生性疾病的分子发病机制中的作用。此外，我们的JAK2V617F敲入小鼠将提供一个独特的可重复性的动物模型，以测试JAK2V617F相关病理的新治疗方法。公共卫生相关性：这项建议旨在利用一种新的可诱导JAK2V617F敲入小鼠来研究JAK2V617F突变在MPDS分子发病机制中的作用。所提出的研究将对MPDS的分子机制提供重要的新见解。这些研究的结果可能会确定MPDS的新治疗靶点。此外，我们的可诱导JAK2V617F敲入小鼠将提供一个独特且可重复性的动物模型来测试JAK2V617F相关MPD的新疗法。