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: 10439570
• 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/10439570
• 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; Persons; 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; antagonist; anti-tumor immune response; autocrine; cytokine; disease phenotype; inhibitor; 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)是各种骨髓增生性肿瘤(MPN)中最致命的，它影响着 美国大约有15万人。MPN的特征是异常 一个或多个血统的增殖，骨髓纤维化，脾肿大，以及 进展为急性髓系白血病。这些基因重复性突变的鉴定 患者，最常见的是JAK2V617F突变，在95%的真性红细胞增多症中发现 (PV)和65%的原发MF(PMF)患者，提示一种常见的分子发病机制 集中在异常的JAK/STAT信号上；然而，JAK抑制剂本身只能提供适度的 临床受益，无法治愈。JAK抑制剂与其他致癌抑制剂的联合应用 AKT、MEK/ERK、mTOR或Hedgehog(HH)等通路显示出比JAK更好的疗效 单独的抑制剂，这表明一个复杂的信号网络驱动MPN。在我的K08期间 在获奖期内，我们已经证明：1)JAK2V617F转基因小鼠表现出增加 SonicHh(Shh)配体的表达及Smo/HH信号的激活2) 使用HH/SMO抑制剂PF-04449913(PF-913，格拉斯迪布)治疗，可降低 脾肿大、细胞因子产生、骨髓纤维化和JAK2V617F等位基因负荷3) JAK2V617F转基因组织表现出MAPK和NFKB信号的增强以及 4)JAK2V617F突变细胞引起HH配体 基质细胞中HH靶基因的依赖激活与转化生长因子-β/Smad2信号转导 因此，我们假设Hedgehog信号对JAK2V617F驱动是必不可少的 疾病和代表和重要的治疗靶点。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 骨髓微环境中异常HH信号的旁分泌效应。我们将专注于 了解转化生长因子-β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名为成像质量的突破性成像技术 细胞术，以40+参数表征旁分泌信号事件和免疫 推动纤维化反应的反应。了解突变型JAK之间的相互作用 信号和Hedgehog信号具有超越MPN的含义，如异常的JAK/STAT和 Hedgehog信号与许多癌症和非癌症有关。 自身免疫性疾病、移植物抗宿主病、炎症和肝脏 肝硬变。

项目成果

Single-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma.

• DOI: 10.1182/bloodadvances.2022007493
• 发表时间: 2022-08-23
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Colombo, Anthony R;Hav, Monirath;Singh, Mohan;Xu, Alexander;Gamboa, Alicia;Lemos, Tucker;Gerdtsson, Erik;Chen, Denaly;Houldsworth, Jane;Shaknovich, Rita;Aoki, Tomohiro;Chong, Lauren;Takata, Katsuyoshi;Chavez, Elizabeth A;Steidl, Christian;Hicks, James;Kuhn, Peter;Siddiqi, Imran;Merchant, Akil
• 通讯作者: Merchant, Akil