Identifying the Role of the IL-6/STAT3 Signaling Pathway in Higher-risk Myelodysplastic Syndrome

确定 IL-6/STAT3 信号通路在高危骨髓增生异常综合征中的作用

• 批准号: 10367220
• 负责人: Maria Laura Amaya
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367220
• 关键词: Acute Myelocytic Leukemia; Adverse effects; Biological Assay; Candidate Disease Gene; Cell Survival; Cells; Clinical; Data; Development; Diagnosis; Disease; Dysmyelopoietic Syndromes; Elderly; Electron Transport; Engraftment; Gene Expression; Genes; Genetic; Genus Hippocampus; Goals; Human; IL-6 inhibitor; IL6ST gene; Immune; Inflammation; Inflammatory; Interleukin Activation; Interleukin-6; International; Link; Malignant Neoplasms; Metabolic; Methods; Mitochondria; Mitochondrial Proteins; Molecular Genetics; Mus; Myeloproliferative disease; Nuclear; Outcome; Oxidative Phosphorylation; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Pharmacology; Phosphorylation; Phosphorylation Site; Production; Prognosis; Property; Proteins; Regulation; Research; Respiration; Risk; Role; STAT6 Transcription Factor; Sampling; Serine; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Stat3 protein; Supportive care; Survival Rate; System; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Tissues; Xenograft procedure; acute myeloid leukemia cell; base; cancer cell; high risk; improved; in vivo Model; leukemic stem cell; metabolomics; novel therapeutic intervention; prevent; prognostic; stem cell population; stem cell survival; stem cells; tool; transcription factor

Myelodysplastic syndromes (MDS) are myeloid malignancies most commonly diagnosed at an advanced age. They are considered a spectrum of malignancies that can range from low to high grade and they are classified based on an international prognostic system. This prognostic system separates them into a range from very low risk with survival rates of several years to very high risk with survival rates of less than a year. Therapeutic interventions have focused on targeting higher risk MDS (from intermediate to very high risk), as the benefit of disease-modifying therapies far outweighs the risk of adverse effects from such therapies. Research aimed at developing targets for this disease has described the presence of a subpopulation of leukemia stem cells, which give rise to the disease and are therefore a critical target to eradicate this malignancy. Prior studies have defined metabolic properties of leukemia stem cells, including their reliance in mitochondrial function and oxidative phosphorylation; therefore, targeting oxidative phosphorylation is a potential avenue for eliminating this subpopulation within MDS cells. There are currently very limited therapies aimed at targeting leukemia stem cells, and this is an unmet need in this field. The candidate’s long-term goal will be to develop new therapeutic strategies aimed at targeting this subpopulation. The hypothesis of this study is that signal transducer and activator of transcription 3 (STAT3) regulates mitochondrial function of leukemia stem cells via regulation of several nuclear-encoded genes that are crucial for proper function of the mitochondria, while also translocating to the mitochondria and modulating the function of the electron transport chain. Aim 1 will elucidate whether the IL-6/STAT3 signaling pathway regulates nuclear genes involved in survival of intermediate to very high risk MDS stem cells. Aim 2 will determine whether IL-6/STAT3 signaling regulates the mitochondrial function of higher-risk MDS stem cells. This will be studied by investigating the importance of STAT3 interactions with other proteins in the mitochondria. To determine if either of these roles is essential for survival of leukemia stem cells, Aim 3 will investigate whether targeting IL-6 or STAT3 decreases the engraftment potential of human primary MDS patient samples in immune-deficient mice. Based on these findings, targeting STAT3 and IL-6 will be tested in in vivo models.

骨髓增生异常综合征（MDS）是骨髓恶性肿瘤最常见的诊断在先进的年龄。 它们被认为是恶性肿瘤的一个谱，其范围可以从低到高等级，并且它们被分类为 基于国际预测系统。这个预测系统将它们分为从非常低到 生存率从几年的风险到生存率不到一年的极高风险。治疗 干预措施的重点是针对高风险MDS（从中度到极高风险）， 改善疾病的疗法远远超过了这种疗法的副作用的风险。研究旨在 开发这种疾病的靶点已经描述了白血病干细胞亚群的存在， 引起疾病，因此是根除这种恶性肿瘤的关键目标。先前的研究已经定义了 白血病干细胞的代谢特性，包括它们对线粒体功能和氧化的依赖， 磷酸化;因此，靶向氧化磷酸化是消除这一点的潜在途径。 MDS细胞内的亚群。目前针对白血病干细胞的治疗方法非常有限 细胞，这是该领域未满足的需求。候选人的长期目标将是开发新的治疗方法， 针对这一亚群的战略。本研究的假设是， 转录激活因子3（STAT 3）通过调节线粒体功能调节白血病干细胞 几个核编码的基因对线粒体的正常功能至关重要，同时也易位 并调节电子传递链的功能。目标1将阐明 IL-6/STAT 3信号通路调节核基因参与中高危MDS的生存 干细胞目的2将确定IL-6/STAT 3信号转导是否调节高风险性心肌梗死患者的线粒体功能。 骨髓增生异常综合征干细胞这将通过研究STAT 3与其他蛋白质相互作用的重要性来研究。 线粒体为了确定这两种作用中的任何一种是否对白血病干细胞的存活至关重要，Aim 3将 研究靶向IL-6或STAT 3是否降低人原发性MDS患者的植入潜力 免疫缺陷小鼠的样本。基于这些发现，将在体内测试靶向STAT 3和IL-6 模型