The Role of PTPN11 in Myelofibrosis

PTPN11 在骨髓纤维化中的作用

基本信息

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
项目类别：
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

项目摘要

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.

标题：PTPN11在骨髓纤维化中的作用项目摘要/摘要骨髓纤维化（MF）是最严重的骨髓增生性肿瘤（MPN），其特征是沉积骨髓中的纤维组织，异常的巨型毛毛毛菌和外造成造血。这 MF患者的中位生存期为约5年。 Janus激酶2中的体细胞激活V617F突变（JAK2V617F）已在50-60％的MF患者中发现。编码基因中的其他突变在MF中发现了血小胞生成素受体（MPL）和钙网蛋白（CALR），但频率低于 JAK2V617F。 ruxolitinib是一种JAK1/JAK2抑制剂，已批准用于治疗MF。虽然鲁唑替尼可以减少脾肿大，无法导致MPN/MF患者的疾病缓解或预防纤维化。它已经很清楚，包括JAK2抑制剂在内的当前化学疗法不足以治愈 MPN/MF。因此，迫切需要确定新的治疗靶点并开发新的靶向疗法对于MF。在初步研究中，我们已经确定蛋白质酪氨酸磷酸酶PTPN11是潜力 MF的治疗靶标。我们发现PTPN11在小鼠和人类中被组成型磷酸化 MPN造血细胞/祖细胞。 PTPN11的敲低显着抑制细胞的增殖表示JAK2V617F。在初步研究中，使用条件PTPN11敲除和JAK2V617F敲入小鼠，我们已经观察到PTPN11的缺失可防止PV的发展并明显抑制骨髓纤维化。我们还观察到，PTPN11的药理抑制显着抑制了生长 JAK2V617F阳性MPN细胞的摄入量，并显着降低了JAK2V617F敲入中的骨髓纤维化老鼠。因此，我们假设PTPN11在MF的发病机理中可能起重要作用，并抑制 PTPN11可能可用于治疗MPN/MF。为了检验我们的假设，我们提出了三个特定的特定目标。在AIM 1中，我们将研究PTPN11在骨髓纤维化（MF）的发病机理中的作用。在AIM 2中，我们将确定PTPN11对MPN细胞/祖细胞和MPN/MF动物模型的疗效。在AIM 3中，我们将确定PTPN11耗竭或抑制阻止发展的机制/ MPN/MF的进展。我们提出的研究将提供首次证明PTPN11扮演在MF的发病机理和PTPN11的抑制中，重要作用是MF的一种新型治疗方法。我们还将对PTPN11如何促进MF的发展有机械理解。结果这些研究应导致I/II期临床试验的设计，该试验涉及PTPN11抑制剂以治疗 MPN/MF。