Targeting Novel Pathways in JMML

针对 JMML 中的新途径

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要幼年型粒单核细胞白血病（JMML）是儿童期常见的骨髓增生性肿瘤（MPN）。由于 NF1、CBL、KRAS、NRAS 或 PTPN11 和细胞中的突变，JMML 的特点是由 Ras 驱动 JMML 患者对 GM-CSF 过敏，化疗药物对 JMML 大多无效。唯一的治疗方法是临床常见的异基因造血干细胞移植（HSCT）。 JMML 中的图片是它表现为一种过度炎症综合征，并且通常很难与因此，JMML 的一个组成部分与高炎症状态和先天性过度活跃有关。此外，与其他 MPN 不同，JMML 很少进展为急变，而是由于死亡。重要的是，同种异体 HSCT 后，50% 的髓外骨髓细胞扩张会导致器官衰竭。患者死于白血病复发，暗示骨髓微环境 (BME) 在 JMML 中的作用 JMML 的高炎症性质可能会损害 BME，改变 BME。移植后正常供体细胞的扩增，使残留的白血病细胞能够战胜正常细胞利用 JMML 小鼠模型，我们证明携带 PTPN11 的小鼠会出现复发。突变，我们显示了携带 PTPN11 的小鼠中 BME 的组成发生了改变，并提供了 JMML 的证据 HSCT 时中性粒细胞计数较高的患者更有可能复发。先前的研究表明，PTPN11 突变导致中性粒细胞过度活跃和发炎，表明这些细胞可能会导致复发，我们将对此进行详细分析。在 JMML 中差异表达的 lncRNA 的测序数据集在此过程中，我们确定了几个。我们将研究其中一种 lncRNA 的表达受到差异调节。我们最近发现 PI3K 催化亚基 p110δ 有助于 JMML 发病机制。 Akt 和 Erk 过度激活，并促进 PTPN11 诱导的 GM-CSF 超敏反应过度增殖，因此在缺乏完全救援的情况下部分促进了 JMML 的进展。由于 PTPN11 诱导的 JMML 中 p110δ 丢失，我们找到了与 p110δ 一起发出信号的推定酪氨酸激酶我们提供了最佳 JMML 治疗所必须针对的 PI3K-Akt 信号通路中的一个。证明 Bruton 的酪氨酸激酶 (BTK) 抑制与 PI3K p110δ 抑制协同作用，以减少我们将研究这种合作背后的机制。总体而言，拟议的目标将为 JMML 的发展和发病机制以及识别新的治疗靶点。