Role of Hedgehog Signaling in JAK2V617F Associated Myelofibrosis

Hedgehog 信号转导在 JAK2V617F 相关骨髓纤维化中的作用

• 批准号: 9916647
• 负责人: Akil Merchant
• 金额: $ 42.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916647
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Alleles; Animal Model; Autoimmune Diseases; Award; Binding; Blood; Bone Marrow; Cells; Chronic Kidney Failure; Clinical; Complex; Cytometry; Disease; Embryonic Development; Erinaceidae; Event; FRAP1 gene; Fibrosis; Genes; Image; Imaging Techniques; Immune; Immune response; Inflammation; JAK2 gene; Knockout Mice; Ligands; Liver Cirrhosis; MADH2 gene; MAP Kinase Gene; MEKs; Malignant Neoplasms; Marrow; Mediating; Megakaryocytes; Modeling; Molecular; Mus; Mutation; Myelofibrosis; Myeloid Cells; Myeloproliferative disease; NF-kappa B; Non-Malignant; Oncogenic; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Phenotype; Polycythemia Vera; Primary Myelofibrosis; Production; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Reaction; Recurrence; Regulation; Research; Resolution; Role; SHH gene; Sampling; Signal Transduction; Source; Splenomegaly; Stromal Cells; Therapeutic; Tissues; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; Transplantation; United States; anti-tumor immune response; autocrine; cytokine; disease phenotype; inhibitor/antagonist; injury and repair; mutant; paracrine; promoter; smoothened signaling pathway; targeted treatment; therapeutic target; tumor

Myelofibrosis (MF) is the deadliest of the various myeloproliferative neoplasms (MPN) that affect approximately 150,000 people in the United States. MPN are characterized by abnormal proliferation of one or more of the blood lineages, bone marrow fibrosis, splenomegaly, and progression to acute myeloid leukemia. The identification of recurrent mutations in these patients, the most common being the JAK2V617F mutation found in 95% of polycythemia vera (PV) and 65% of primary MF (PMF) patients, suggests a common molecular pathogenesis centered on aberrant JAK/STAT signaling; however, JAK inhibitors alone offer only modest clinical benefit, without cure. Combinations of JAK inhibitors with other inhibitors of oncogenic pathways such as AKT, MEK/ERK, mTOR, or Hedgehog (Hh), show greater efficacy then JAK inhibitors alone, suggesting that a complex signaling network drives MPN. During my K08 award period, we have demonstrated that: 1) JAK2V617F transgenic mice show increased sonicHh (Shh) ligand expression and activation of Smoothened (Smo)/Hh signaling 2) Treatment with the Hh/Smo inhibitor, PF-04449913 (PF-913, glasdegib), reduces the splenomegaly, cytokine production, marrow fibrosis and JAK2V617F allele burden 3) JAK2V617F transgenic tissues show increased MAPK and NFKB signaling as well as increased TGF-B levels, which decrease with Smo inhibition 4) JAK2V617F mutant cells cause Hh ligand dependent activation of Hh target genes and TGF-B/SMAD2 signaling in stromal cells. Therefore, we hypothesize that Hedgehog signaling is essential for JAK2V617F driven diseases and represents and important therapeutic target. The aims of this study are to determine how JAK2V617F leads to Hh pathway activation and delineate the autocrine vs paracrine effects of abnormal Hh signaling in the bone marrow microenvironment. We will focus on understanding how TGF-B mediates fibrosis and alters the host immune response to MPN. This study will make use of a breakthrough imaging technique known as Imaging Mass Cytometry, to characterize with 40+ parameters the paracrine signaling events and immune response that drives the fibrosis reaction. Understanding the interaction between mutant JAK signaling and hedgehog signaling has implications beyond MPN, as abnormal JAK/STAT and Hedgehog signaling have been implicated in numerous cancers as well as in non-cancerous conditions such as autoimmune diseases, graft verses host disease, inflammation and liver cirrhosis.

骨髓纤维化（MF）是影响骨髓增生性肿瘤（MPN）的各种疾病中最致命的一种。 在美国大约有15万人。MPN的特点是异常 一种或多种血液谱系的增殖，骨髓纤维化，脾肿大，和 进展为急性髓细胞白血病。在这些基因组中鉴定复发性突变 最常见的是在95%的真性红细胞增多症患者中发现的JAK 2 V617 F突变 (PV)和65%的原发性MF（PMF）患者，提示共同的分子发病机制 以异常JAK/STAT信号传导为中心;然而，单独的JAK抑制剂只能提供适度的作用 临床受益，无治愈。JAK抑制剂与其他致癌性肿瘤抑制剂的组合 途径如AKT、MEK/ERK、mTOR或Hedgehog（Hh），显示出比JAK更大的功效 抑制剂单独，这表明一个复杂的信号网络驱动MPN。在我的K 08 在获奖期间，我们已经证明：1）JAK 2 V617 F转基因小鼠表现出增加的 SonicHh（Shh）配体表达和Smothened（Smo）/Hh信号传导的激活2） 使用Hh/Smo抑制剂PF-04449913（PF-913，glasdegib）治疗可降低 脾肿大、细胞因子产生、骨髓纤维化和JAK 2 V617 F等位基因负荷3） JAK 2 V617 F转基因组织显示出增加的MAPK和NF κ B信号传导以及增加的细胞凋亡。 4）JAK 2 V617 F突变细胞引起Hh配体 基质细胞中Hh靶基因和TGF-β/SMAD 2信号传导的依赖性活化。 因此，我们假设Hedgehog信号传导对于JAK 2 V617 F驱动的细胞凋亡是必不可少的。 是疾病的代表和重要的治疗靶点。本研究的目的是 确定JAK 2 V617 F如何导致Hh通路激活，并描述自分泌与 骨髓微环境中异常Hh信号传导的旁分泌效应。我们将重点 了解TGF-B如何介导纤维化和改变宿主对MPN的免疫反应。 这项研究将利用一种突破性的成像技术，称为成像质量 细胞计数，用40多个参数表征旁分泌信号传导事件和免疫 驱动纤维化反应的反应。了解突变JAK之间的相互作用 信号和刺猬信号的影响超出了MPN，因为异常JAK/STAT和 Hedgehog信号与许多癌症和非癌性疾病有关。 诸如自身免疫性疾病、移植物抗宿主病、炎症和肝脏疾病的病症 肝硬化