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Targeting Novel Pathways in JMML

针对 JMML 中的新途径

基本信息

批准号：
10077886
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077886
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.

项目总结/文摘