Targeting Novel Pathways in JMML

针对 JMML 中的新途径

• 批准号: 10324564
• 负责人: Reuben Kapur
• 金额: $ 54.24万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324564
• 关键词: 4 year old; AKT Signaling Pathway; Abnormal Myeloid Cell; Accounting; Agammaglobulinaemia tyrosine kinase; Allogenic; B-Lymphocytes; Binding; Blast Phase; Bone Marrow; CBL gene; CSF2 gene; Catalytic Domain; Cells; Cessation of life; Child; Childhood; Chronic Myeloid Leukemia; Chronic Phase; Clinical; Data; Data Set; Development; Disease Progression; Engraftment; Equilibrium; Extramedullary; Feedback; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hyperactivity; Hypersensitivity; Immune; Individual; Infection; Inflammatory; Innovative Therapy; Juvenile Myelomonocytic Leukemia; KRAS2 gene; Leukemic Cell; Life; Modality; Modeling; Mus; Mutation; Myeloid Cells; Myeloproliferative disease; NF1 gene; Nature; Organ failure; PLCgamma2; PTPN11 gene; Pathogenesis; Pathway interactions; Patients; Pharmacology; Play; Process; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Regulation; Relapse; Residual state; Respiratory Failure; Role; Signal Transduction; Syndrome; Time; Transplant Recipients; Transplantation; Untranslated RNA; Viral; Virus Diseases; chemotherapeutic agent; curative treatments; cytotoxic; differential expression; insight; juvenile myelomonocytic leukemia cell; leukemia; leukemia relapse; mortality; mouse model; mutant; neutrophil; new therapeutic target; novel; overexpression; relapse patients; transcriptome sequencing; transplant model; tumor progression

PROJECT SUMMARY/ABSTRACT Juvenile myelomonocytic leukemia (JMML) is a common myeloproliferative neoplasm (MPN) in childhood. JMML is characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11, and cells from JMML patients show hypersensitivity to GM-CSF. Chemotherapeutic agents are mostly ineffective in JMML, and the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). A common clinical picture in JMML is that it presents as a hyperinflammatory syndrome, and is often difficult to distinguish from viral infections. Thus, a component of JMML is associated with hyperinflammatory state and hyperactive innate immune cells. Further, unlike other MPNs, JMML rarely progresses to blast crisis; rather, mortality is due to extramedullary myeloid cell expansion leading to organ failure. Importantly, following allogeneic HSCT, 50% of patients succumb to leukemia relapse, implicating a role for bone marrow microenvironment (BME) in JMML development and progression. The hyperinflammatory nature of JMML may damage the BME, altering the expansion of normal donor cells following transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to relapse. Utilizing mouse models of JMML, we demonstrate relapse in mice bearing PTPN11 mutations, we show altered composition of the BME in PTPN11 bearing mice and provide evidence that JMML patients that have a higher neutrophil count at the time of HSCT are more likely to relapse. These data combined with previous studies demonstrating hyperactive and inflamed neutrophils due to PTPN11 mutations suggests that these cells may contribute to relapse. We will examine this in detail. We have been analyzing multiple RNA sequencing datasets for lncRNAs that are differentially expressed in JMML. In doing so, we identified several novel lncRNAs whose expression is differentially regulated. We will examine how one of these lncRNAs contributes to JMML pathogenesis. We have recently shown that PI3K catalytic subunit p110δ contributes to both Akt and Erk hyperactivation, and promotes PTPN11-induced GM-CSF hypersensitivity and hyperproliferation, thus partially contributing to the progression of JMML. Given the lack of complete rescue by loss of p110δ in PTPN11-induced JMML, we sought out putative tyrosine kinases that signal together with p110δ in the PI3K-Akt signaling pathway that must be targeted for optimal JMML therapy. We present preliminary data demonstrating that Bruton's Tyrosine Kinase (BTK) inhibition collaborates with PI3K p110δ inhibition to reduce the activation of Akt and Erk in PTPN11-expressing cells. We will study the mechanism behind this cooperation. Overall, the proposed Aims will shed novel insight into JMML development and pathogenesis as well as identification of novel therapeutic targets.

项目摘要/摘要 幼年粒单核细胞白血病(JMML)是儿童常见的骨髓增生性肿瘤(MPN)。 由于NF1、CBL、KRAS、NRAS或PTPN11和细胞的突变，JMML的特征是RAS驱动的 来自JMML患者对GM-CSF表现出超敏反应。化疗药物在JMML中大多无效， 唯一的治愈方法是异基因造血干细胞移植(HSCT)。一个常见的临床 在JMML中，它表现为一种高炎症综合征，通常很难区分 病毒感染。因此，JMML的一种成分与炎症状态和先天的过度活跃有关 免疫细胞。此外，与其他MPN不同，JMML很少进展到爆炸危机；相反，死亡率是由于 髓外髓系细胞扩张导致器官衰竭。重要的是，异基因造血干细胞移植后，50%的 患者死于白血病复发，暗示骨髓微环境(BME)在JMML中的作用 发展和进步。JMML的高炎性可能会损害BME，改变 移植后正常供者细胞的扩增，允许残留的白血病细胞竞争超过正常细胞 贪污，并导致复发。利用JMML小鼠模型，我们展示了携带PTPN11的小鼠的复发 突变，我们显示了携带PTPN11的小鼠BME的组成发生了变化，并提供了JMML 接受HSCT时中性粒细胞计数较高的患者更有可能复发。这些数据加在一起 先前的研究表明，PTPN11突变导致的中性粒细胞过度活跃和炎症 这些细胞可能会导致复发。我们将对此进行详细研究。我们一直在分析多个RNA 对JMML中差异表达的lncRNA的数据集进行测序。在这样做的过程中，我们确定了几个 表达受差异调控的新型lncRNAs。我们将研究其中一个lncRNA是如何 与JMML的发病机制有关。我们最近发现PI3K催化亚基p110δ有助于 Akt和Erk的过度激活，并促进PTPN11诱导的GM-CSF超敏反应和 过度扩散，从而部分促成了JMML的进展。考虑到缺乏完全的救援， 在pPTPN11诱导的JMML中p110δ的丢失，我们寻找了与p110δ一起发出信号的可能的酪氨酸激酶 在PI3K-Akt信号通路中，JMML的最佳治疗必须以此为靶点。我们给出了初步数据 证明布鲁顿的酪氨酸激酶抑制与PI3K p110δ抑制协同作用 PTPN11表达细胞中Akt和Erk的激活。我们将研究这一合作背后的机制。 总体而言，提出的目标将为JMML的发展和发病机制以及 确定新的治疗靶点。