Role of JAK2V617F in the Pathogenesis of Myeloproliferative Disorders.

描述（由申请方提供）：骨髓增生性疾病（MPD）是一种克隆性恶性血液病，特征为一种或多种髓系细胞过度产生。在MPD中经常观察到染色体易位或蛋白酪氨酸激酶突变。例如，费城染色体易位的产物BCR-ABL与慢性髓性白血病（CML）相关。Ets家族转录因子TEL与血小板衍生生长因子受体β（PDGFR 2）的融合导致慢性粒单核细胞白血病（CMML）。Janus激酶2（JAK 2）的体细胞点突变（V617 F）已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。小鼠骨髓移植和JAK 2 V617 F转基因模型证明了JAK 2活化在MPD发病机制中的重要性。然而，仍然难以理解单个JAK 2 V617 F等位基因如何产生具有不同临床特征的三种不同MPD- PV、ET和PMF。此外，JAK 2 V617 F的信号传导要求和转化/MPD的精确机制在很大程度上仍然未知。在初步研究中，我们已经开发了一种新的诱导型JAK 2 V617 F基因敲入小鼠。我们将使用这种诱导型敲入小鼠来确定JAK 2 V617 F在MPD中的作用。我们将研究JAK 2 V617 F基因剂量（杂合性与纯合性）对MPD表型的影响。我们将测试不同祖细胞的转化是否导致不同的MPD。我们还将评估遗传背景/宿主修饰剂对MPD发病机制的潜在贡献。使用遗传方法，我们还将确定JAK 2 V617 F介导的转化/MPD的信号传导要求。这些研究将有助于更好地理解JAK 2 V617 F在骨髓增生性疾病分子发病机制中的作用。此外，我们的JAK 2 V617 F基因敲入小鼠将提供一种独特且可重复的动物模型，以测试JAK 2 V617 F相关病理的新治疗方法。公共卫生相关性：本研究的目的是利用一种新的JAK 2 V617 F基因敲入小鼠研究JAK 2 V617 F突变在MPD分子发病机制中的作用。这些研究将为深入了解MPDs的分子机制提供重要的新见解。这些研究的结果可能会为MPD确定新的治疗靶点。此外，我们的诱导型JAK 2 V617 F敲入小鼠将提供独特且可再现的动物模型来测试JAK 2 V617 F相关MPD的新疗法。

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.