The Role of PTPN11 in Myelofibrosis

PTPN 11在骨髓纤维化中的作用 项目概要/摘要 骨髓纤维化（MF）是骨髓增生性肿瘤（MPN）中最严重的一种，其特征是 骨髓纤维组织增生异常、异常巨核细胞生成和髓外造血。的 MF患者的中位生存期约为5年。Janus激酶2的体细胞激活V617 F突变 在50-60%的MF患者中发现了JAK 2 V617 F。基因编码的其他突变 血小板生成素受体（MPL）和钙网蛋白（CALR）在MF中被发现，但频率低于 JAK2V617F. Ruxolitinib是一种JAK 1/JAK 2抑制剂，已被批准用于治疗MF。虽然Ruxolitinib 但不能缓解MPN/MF患者的病情或预防纤维化。它 已经很清楚，目前的化疗，包括JAK 2抑制剂是不足以治愈 MPN/MF。因此，寻找新的治疗靶点，开发新的靶向治疗方法，成为当前研究的热点 对于MF。在初步研究中，我们已经确定蛋白酪氨酸磷酸酶PTPN 11作为一种潜在的 MF的治疗靶点。我们已经发现PTPN 11在小鼠和人类中是组成性磷酸化的， MPN造血细胞/祖细胞。PTPN 11的敲低显著抑制细胞增殖 表达JAK 2 V617 F。在初步研究中，使用条件性PTPN 11敲除和JAK 2 V617 F敲入， 在小鼠中，我们观察到PTPN 11的缺失阻止了PV的发展，并显著抑制了PV的发生。 骨髓纤维化我们还观察到PTPN 11的药理学抑制显著抑制了细胞的生长， JAK 2 V617 F-阳性MPN细胞的表达，并显著降低JAK 2 V617 F基因敲入的骨髓纤维化 小鼠因此，我们推测PTPN 11可能在MF的发病机制中起重要作用，并且抑制PTPN 11的表达可能是MF发病的重要机制之一。 PTPN 11可能对MPN/MF的治疗有一定的作用。为了验证我们的假设，我们提出了三个具体的假设。 目标。在目的1中，我们将研究PTPN 11在骨髓纤维化（MF）发病机制中的作用。在目标2中， 将确定PTPN 11抑制对MPN细胞/祖细胞和MPN/MF动物模型的功效。 在目标3中，我们将确定PTPN 11耗尽或抑制阻断发展的机制。 MPN/MF的进展。我们提出的研究将首次证明PTPN 11在肿瘤发生中起着重要作用。 PTPN 11在MF发病机制中的重要作用和抑制PTPN 11是MF的一种新的治疗方法。我们 还将对PTPN 11如何促进MF的发展有机械的理解。结果 这些研究应导致设计一项涉及PTPN 11抑制剂治疗以下疾病的I/II期临床试验： MPN/MF。

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.