Role of JAK2V617F in the Pathogenesis of Myeloproliferative Neoplasms

JAK2V617F 在骨髓增生性肿瘤发病机制中的作用

• 批准号: 9566613
• 负责人: Golam Mohi
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9566613
• 关键词: Role; JAK2V617F; Pathogenesis; Myeloproliferative; Neoplasms

 DESCRIPTION (provided by applicant): Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a group of chronic hematologic malignancies characterized by the overproduction of myeloid lineage cells. The JAK2V617F mutation has been found in ~95% cases of PV and 50-60% cases of ET and PMF However, the contribution of JAK2V617F in these three different MPNs still remains unclear. Using an inducible JAK2V617F knock-in mouse, we have shown that expression of heterozygous JAK2V617F in hematopoietic compartments is sufficient to cause a PV-like disease whereas homozygous JAK2V617F expression accelerates the progression to myelofibrosis (MF). We also have shown that only JAK2V617F-expressing hematopoietic stem cells (HSCs) have the capacity to self-renew and propagate the MPN disease. However, the actual role of JAK2V617F in HSCs has remained unclear and controversial. Most studies are focused on the bone marrow (BM) HSC function. The contribution of spleen HSCs in the maintenance of JAK2V617F-evoked MPN remains unknown. We have found that the number of HSCs in the BM is reduced over time while spleen HSC pool is consistently increased in JAK2V617F knock-in mice. We hypothesize that JAK2V617F expression may cause aberrant HSC function, and JAK2V617F-expressing spleen HSCs may play an important role in the long-term maintenance of MPNs. JAK2 inhibitor therapy exhibits some benefits to the MPN patients but results in significant hematopoietic toxicities since JAK2 is critical for normal hematopoietic development. Identification of the targets of JAK2V617F in HSCs that are required for MPN but are not essential for normal hematopoietic development would facilitate the development of new targeted and safer therapies for MPNs. In preliminary studies, using microarray gene expression profiling, we have identified several targets of JAK2V617F in HSCs. Therefore, Aim 1 will determine the effects of JAK2V617F on BM and spleen HSCs, and identify the downstream targets of JAK2V617F in HSCs that are required for MPN. Although JAK2V617F is the most common mutation found in MF, the mechanisms of MF induced by JAK2V617F remains unknown. We have found that Shp2 is constitutively phosphorylated in JAK2V617F- positive MPN/leukemia patient derived cell lines and in the BM of JAK2V617F knock-in mice. In preliminary studies, we have found that deletion of Shp2 inhibits PV and prevents the development of MF in JAK2V617F mice. We hypothesize that Shp2 may play an important role in the pathogenesis of PV and MF induced by JAK2V617F. Therefore, Aim 2 will define the role of Shp2 in PV and MF induced by JAK2V617F. Inactivating EZH2 mutations have been found in patients with MF. Moreover, a significant proportion of EZH2 mutated MF patients harbor the JAK2V617F mutation. We hypothesize that EZH2 deficiency may contribute to the phenotypic diversity in JAK2V617F-positive MPNs. In Aim 3, we will determine the contribution of EZH2 deficiency in JAK2V617F-evoked MPN. Collectively, these studies will provide important new insights into the molecular pathogenesis of MPNs and may identify new therapeutic targets for treatment of MPNs.

 描述（由申请方提供）：骨髓增生性肿瘤（MPN）包括真性红细胞增多症（PV）、原发性血小板增多症（ET）和原发性骨髓纤维化（PMF），是一组以髓系细胞过度生成为特征的慢性恶性血液病。JAK 2 V617 F突变已在约95%的PV病例和50-60%的ET和PMF病例中发现，然而，JAK 2 V617 F在这三种不同的MPN中的贡献仍不清楚。使用可诱导的JAK 2 V617 F基因敲入小鼠，我们已经表明，造血区室中杂合JAK 2 V617 F的表达足以引起PV样疾病，而纯合JAK 2 V617 F表达加速骨髓纤维化（MF）的进展。我们还表明，只有JAK 2 V617 F表达造血干细胞（HSC）具有自我更新和繁殖MPN疾病的能力。然而，JAK 2 V617 F在HSC中的实际作用仍然不清楚且存在争议。大多数研究集中在骨髓（BM）HSC功能。脾HSC在维持JAK 2 V617 F诱发的MPN中的作用尚不清楚。我们已经发现，在JAK 2 V617 F敲入小鼠中，BM中HSC的数量随着时间的推移而减少，而脾HSC库持续增加。我们推测JAK 2 V617 F的表达可能导致HSC功能异常，表达JAK 2 V617 F的脾HSC可能在MPN的长期维持中起重要作用。JAK 2抑制剂治疗对MPN患者表现出一些益处，但导致显著的造血毒性，因为JAK 2对正常造血功能至关重要。 发展鉴定MPN所需但不是正常造血发育所必需的HSC中JAK 2 V617 F的靶点将促进MPN的新靶向和更安全疗法的开发。在初步研究中，使用微阵列基因表达谱，我们已经确定了几个目标的JAK 2 V617 F在HSC。因此，目标1将确定JAK 2 V617 F对BM和脾HSC的作用，并鉴定MPN所需的HSC中JAK 2 V617 F的下游靶标。虽然JAK 2 V617 F是MF中最常见的突变，但JAK 2 V617 F诱导MF的机制尚不清楚。我们已经发现，Shp 2在JAK 2 V617 F阳性MPN/白血病患者衍生的细胞系和JAK 2 V617 F敲入小鼠的BM中组成性磷酸化。在初步研究中，我们发现Shp 2的缺失抑制PV并防止JAK 2 V617 F小鼠中MF的发展。我们推测Shp 2可能在JAK 2 V617 F诱导的PV和MF的发病机制中起重要作用。因此，目的2将定义Shp 2在由JAK 2 V617 F诱导的PV和MF中的作用。在MF患者中发现了失活EZH 2突变。此外，相当比例的EZH 2突变的MF患者携带JAK 2 V617 F突变。我们推测EZH 2缺陷可能导致JAK 2 V617 F阳性MPN的表型多样性。在目的3中，我们将确定EZH 2缺陷在JAK 2 V617 F诱发的MPN中的贡献。总的来说，这些研究将为MPN的分子发病机制提供重要的新见解，并可能为MPN的治疗确定新的治疗靶点。