The Role of PTPN11 in Myelofibrosis

PTPN11 在骨髓纤维化中的作用

• 批准号: 10545076
• 负责人: Golam Mohi
• 金额: $ 39.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545076
• 关键词: Animal Model; Applications Grants; Bone Marrow; Cell Line; Cell Lineage; Cells; Data; Deposition; Development; Disease remission; Exhibits; Extramedullary Hematopoiesis; Fibrosis; Frequencies; Gene Expression Profiling; Genes; Goals; Growth; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Heterozygote; Human; Inhibition of Cell Proliferation; JAK1 gene; JAK2 gene; Knock-in; Knock-in Mouse; Knock-out; LoxP-flanked allele; MPL gene; Mediating; Megakaryocytopoieses; Molecular; Mus; Mutation; Myelofibrosis; Myelogenous; Myeloproliferative disease; PTPN11 gene; Pathogenesis; Patients; Penetrance; Phase I/II Clinical Trial; Phosphorylation; Placebos; Play; Polycythemia Vera; Pre-Clinical Model; Production; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Role; Signal Transduction; Splenomegaly; Testing; Therapeutic; Time; Tissues; calreticulin; chemotherapy; design; efficacy evaluation; efficacy testing; expectation; inhibitor; insight; knock-down; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; prevent; progenitor; small hairpin RNA; therapeutic target; transcriptome sequencing

Title: The Role of PTPN11 in Myelofibrosis Project Summary/Abstract Myelofibrosis (MF) is the most severe form of myeloproliferative neoplasm (MPN), characterized by deposition of fibrous tissues in the bone marrow, abnormal megakaryopoiesis, and extramedullary hematopoiesis. The median survival for patients with MF is ~5 years. A somatic activating V617F mutation in the Janus Kinase 2 (JAK2V617F) has been found in 50-60% patients with MF. Additional mutations in the genes encoding thrombopoietin receptor (MPL) and calreticulin (CALR) have been found in MF but at a lower frequency than JAK2V617F. Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for treatment of MF. Although Ruxolitinib can reduce splenomegaly, it failed to produce disease remission or prevent fibrosis in patients with MPN/MF. It has already become clear that current chemotherapies including JAK2 inhibitors are not sufficient to cure MPN/MF. So, there is a critical need to identify new therapeutic target(s) and develop novel targeted therapies for MF. In preliminary studies, we have identified protein tyrosine phosphatase PTPN11 as a potential therapeutic target in MF. We have found that PTPN11 is constitutively phosphorylated in mouse and human MPN hematopoietic cells/progenitors. Knockdown of PTPN11 significantly inhibits proliferation of cells expressing JAK2V617F. In preliminary studies, using conditional PTPN11 knockout and JAK2V617F knock-in mice, we have observed that deletion of PTPN11 prevents the development of PV and markedly inhibits myelofibrosis. We also have observed that pharmacologic inhibition of PTPN11 significantly inhibits the growth of JAK2V617F-positive MPN cells and markedly reduces the bone marrow fibrosis in JAK2V617F knock-in mice. So, we hypothesize that PTPN11 may play an important role in the pathogenesis of MF, and inhibition of PTPN11 might be useful for treatment of MPN/MF. To test our hypothesis, we have proposed three specific aims. In Aim 1, we will investigate the role of PTPN11 in the pathogenesis of myelofibrosis (MF). In Aim 2, we will determine the efficacy of PTPN11 inhibition against MPN cells/progenitors and animal models of MPN/MF. In Aim 3, we will determine the mechanism by which PTPN11 depletion or inhibition blocks the development/ progression of MPN/MF. Our proposed studies will provide the first demonstration that PTPN11 plays an important role in the pathogenesis of MF and inhibition of PTPN11 is a novel therapeutic approach in MF. We will also have mechanistic understanding on how PTPN11 contributes to the development of MF. Results from these studies should lead to the design of a Phase I/II clinical trial involving PTPN11 inhibitor for treatment of MPN/MF.

PTPN11在骨髓纤维化中的作用 项目摘要/摘要 骨髓纤维化(MF)是骨髓增生性肿瘤(MPN)中最严重的一种，以沉积为特征 骨髓中的纤维组织、异常巨核细胞生成和髓外造血。这个 中位生存期为5年。Janus Kinase 2中一个体细胞激活的V617F突变 在50-60%的MF患者中发现了(JAK2V617F)。编码基因的额外突变 血小板生成素受体(MPL)和钙网蛋白(CALR)在MF中被发现，但出现的频率低于 JAK2V617F。Ruxolitinib是一种JAK1/JAK2抑制剂，已被批准用于治疗MF。虽然鲁索利替尼 能缩小脾肿大，但不能缓解MPN/MF患者的病情或预防纤维化。它 已经很清楚，目前包括JAK2抑制剂在内的化疗不足以治愈 MPN/MF。因此，迫切需要确定新的治疗靶点(S)，并开发新的靶向治疗 对于MF。在初步研究中，我们已经确定蛋白酪氨酸磷酸酶PTPN11是一种潜在的 MF的治疗靶点。我们已经发现PTPN11在小鼠和人中是结构性磷酸化的 MPN造血细胞/祖细胞。PTPN11基因敲除显著抑制细胞增殖 表达JAK2V617F。在初步研究中，使用条件性PTPN11基因敲除和JAK2V617F敲入 在小鼠身上，我们观察到PTPN11的缺失阻止了PV的发展，并明显抑制了 骨髓纤维化。我们还观察到，PTPN11的药物抑制显著抑制了细胞的生长 抑制JAK2V617F阳性的MPN细胞，显著减轻JAK2V617F基因敲除小鼠的骨髓纤维化 老鼠。因此，我们推测PTPN11可能在MF的发病机制中起重要作用，并且抑制PTPN11的表达 PTPN11可用于MPN/MF的治疗。为了验证我们的假设，我们提出了三个具体的 目标。目的1，我们将探讨PTPN11在骨髓纤维化(MF)发病机制中的作用。在目标2中，我们 将确定抑制PTPN11对MPN细胞/祖细胞和MPN/MF动物模型的疗效。 在目标3中，我们将确定PTPN11耗尽或抑制阻止发育/的机制。 MPN/MF的研究进展我们提议的研究将提供第一个证明PTPN11在 抑制PTPN11在MF的发病机制中起重要作用，是治疗MF的新途径。我们 也将对PTPN11如何促进MF的发展有机械性的理解。结果来自 这些研究应该导致设计一项涉及PTPN11抑制剂的I/II期临床试验，用于治疗 MPN/MF。