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.

项目摘要/摘要少年脊髓细胞性白血病（JMML）是儿童时期常见的骨髓增生性肿瘤（MPN）。 JMML的特征是由于NF1，CBL，KRAS，NRAS或PTPN11的突变而被RAS驱动，并且细胞是由RAS驱动的。来自JMML患者表现出对GM-CSF的过敏性。化学治疗剂在JMML中大多无效，唯一的治疗方法是同种异性造血干细胞移植（HSCT）。常见的临床 JMML中的图片是它作为一种高炎性综合征，通常很难区分病毒感染。这是JMML的一个组成部分与高炎症状态和过度活跃的先天性有关免疫细胞。此外，与其他MPN不同，JMML很少发生爆炸危机。相反，死亡率是由于外髓样细胞的膨胀导致器官衰竭。重要的是，遵循同种异体HSCT，50％患者屈服于白血病接力赛，暗示了JMML中骨髓微环境（BME）的作用发展和发展。 JMML的过度炎性性可能会损坏BME，从而改变移植后正常供体细胞的扩展，允许残留的白血病细胞胜过正常移植物，并导致救济。利用JMML的鼠标模型，我们演示了带有PTPN11的小鼠中的继电器突变，我们显示了PTPN11轴承小鼠BME的组成改变，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中继。这些数据合并先前的研究表明，由于PTPN11突变引起的过度活跃和发炎的中性粒细胞表明这些细胞可能有助于退休。我们将详细检查一下。我们一直在分析多个RNA 在JMML中以不同表达的LNCRNA的测序数据集。在这样做的过程中，我们确定了几个新型lncrnas的表达受到差异调节。我们将研究这些lncrnas之一有助于JMML发病机理。我们最近表明，PI3K催化亚基P110Δ有助于 AKT和ERK过度激活，并促进PTPN11诱导的GM-CSF超敏反应和高增殖，因此部分促进了JMML的进展。考虑到缺乏完全的救援 PTPN11诱导的JMML中p110Δ的丢失，我们感觉到了推定的酪氨酸激酶，这些激酶与p110δ一起信号在PI3K-AKT信号通路中，必须针对最佳JMML治疗。我们提出初步数据证明布鲁顿的酪氨酸激酶（BTK）抑制与PI3KP110Δ抑制作用以减少在表达PTPN11的细胞中Akt和ERK的激活。我们将研究这种合作背后的机制。总体而言，拟议的目标将使对JMML发育和发病机理以及鉴定新的治疗靶标。