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（由适用提供）：包括多性炎性疗法（PV），必需血小板细胞增多症（ET）和原发性骨髓纤维纤维化（PMF），是一组慢性血液学恶性肿瘤，由骨髓细胞细胞的过度生产表征。在〜95％的PV病例和50-60％的ET和PMF病例中发现了JAK2V617F突变，但是，这三种不同MPN中JAK2V617F的贡献仍然不清楚。使用可诱导的JAK2V617F敲入小鼠，我们表明杂合子JAK2V617F在造血室中的表达足以引起PV类疾病，而纯合JAK2V617F表达会加速向骨髓纤维症（MF）加速。我们还表明，仅表达JAK2V617F的造血干细胞（HSC）具有自我更新和传播MPN疾病的能力。但是，JAK2V617F在HSC中的实际作用尚不清楚和有争议。大多数研究都集中在骨髓（BM）HSC功能上。脾脏HSC在维持JAK2V617F诱发的MPN中的贡献尚不清楚。我们发现，随着时间的推移，BM中的HSC数量减少，而在JAK2V617F敲门小鼠中，Spleen HSC池始终增加。我们假设JAK2V617F表达可能会导致异常HSC功能，而表达表达JAK2V617F的脾脏HSC可能在MPN的长期维持中起重要作用。 JAK2抑制剂疗法对MPN患者表现出一些好处，但由于JAK2对正常造血至关重要，因此会导致明显的造血毒性 发展。 MPN所需的HSC中JAK2V617F的靶标的鉴定，但对于正常的造血发展并不是必不可少的，这将支持对MPN的新靶向和更安全的疗法的发展。在初步研究中，使用微阵列基因表达分析，我们确定了HSC中JAK2V617F的几个靶标。因此，AIM 1将确定JAK2V617F对BM和Spleen HSC的影响，并确定MPN所需的HSC中JAK2V617F的下游靶标。尽管JAK2V617F是MF中最常见的突变，但JAK2V617F诱导的MF机制仍然未知。我们发现，在JAK2V617F-阳性MPN/白血病患者衍生的细胞系和JAK2V617F敲击小鼠的BM中，SHP2始终被磷酸化。在初步研究中，我们发现SHP2的缺失抑制了PV并防止JAK2V617F小鼠中MF的发展。我们假设SHP2可能在JAK2V617F诱导的PV和MF的发病机理中起重要作用。因此，AIM 2将定义SHP2在JAK2V617F诱导的PV和MF中的作用。在MF患者中发现了EZH2突变。此外，很大一部分EZH2突变的MF患者含有JAK2V617F突变。我们假设EZH2缺乏症可能有助于JAK2V617F阳性MPN的表型多样性。在AIM 3中，我们将确定EZH2缺乏在JAK2V617F诱发的MPN中的贡献。总的来说，这些研究将为MPN的分子发病机理提供重要的新见解，并可能确定用于治疗MPN的新治疗靶标。