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: 10202699
• 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/10202699
• 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 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; tissue injury; tumor; tumor-immune system interactions

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）是影响影响的各种骨髓增生性肿瘤（MPN）中最致命的 美国约有15万人。 MPN的特征是异常 一个或多个血统，骨髓纤维化，脾肿大和 发展为急性髓样白血病。在这些中识别复发突变 患者，最常见的是JAK2V617F突变，在95％的多性性无体性Vera中发现 （PV）和65％的原发性MF（PMF）患者表明一种常见的分子发病机理 以异常的jak/stat信号为中心；但是，仅JAK抑制剂仅提供适中 临床益处，无法治愈。 JAK抑制剂与其他致癌抑制剂的组合 诸如AKT，MEK/ERK，MTOR或HEDGEHOG（HH）之类的途径显示出比JAK更大的功效 仅抑制剂，表明复杂的信号网络驱动MPN。在我的K08期间 奖励期，我们已经证明：1）JAK2V617F转基因小鼠显示增加 Sonichh（SHH）配体表达和平滑（SMO）/HH信号的激活2） 用HH/SMO抑制剂PF-04449913（PF-913，Glasdegib）处理，减少了 脾肿大，细胞因子产生，骨髓纤维化和JAK2V617F等位基因负担3） JAK2V617F转基因组织显示MAPK和NFKB信号增加以及增加 TGF-B水平，随着SMO抑制作用而降低4）JAK2V617F突变细胞引起HH配体 基质细胞中HH靶基因和TGF-B/SMAD2信号的依赖激活。 因此，我们假设刺猬信号对于JAK2V617F驱动至关重要 疾病和代表和重要的治疗靶标。这项研究的目的是 确定JAK2V617F如何导致HH途径激活并描绘自分泌与 骨髓微环境中HH信号异常的旁分泌作用。我们将集中精力 了解TGF-B如何介导纤维化并改变宿主对MPN的免疫反应。 这项研究将利用一种被称为成像质量的突破性成像技术 细胞仪，以40+参数为特征，旁分泌信号事件和免疫 驱动纤维化反应的反应。了解突变jak之间的相互作用 信号传导和刺猬信号传导的含义超出了MPN，如jak/stat和 刺猬信号已与许多癌症以及非癌症有关 诸如自身免疫性疾病，移植经文宿主疾病，炎症和肝脏等疾病 肝硬化。