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

骨髓增生异常综合征(MDS)是一种髓系恶性肿瘤，通常在高龄时被诊断出来。 它们被认为是一种从低级别到高级别的恶性肿瘤，并被分类 基于一个国际预测系统。这个预测系统将他们分成从很低到很低的范围 存活率为几年的风险到存活率不到一年的非常高的风险。治疗性的 干预措施的重点是针对较高风险的MDS(从中等风险到极高风险)，因为 疾病修正疗法远远超过此类疗法带来的不良影响风险。研究的目的是 针对这种疾病的开发靶点描述了白血病干细胞亚群的存在，这一亚群 导致这种疾病，因此是根除这种恶性疾病的关键目标。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种现象的潜在途径。 MDS细胞内的亚群。目前针对白血病干细胞的治疗非常有限。 细胞，这是这一领域尚未得到满足的需求。候选人的长期目标将是开发新的治疗方法 旨在针对这一群体的战略。这项研究的假设是信号转换器和 转录激活因子3(STAT3)调节白血病干细胞线粒体功能 几个核编码基因，对线粒体的正常功能至关重要，同时也是移位 并调节电子传输链的功能。目标1将阐明是否 IL-6/STAT3信号通路调控与中高危MDS生存相关的核基因 干细胞。目的2将确定IL-6/STAT3信号是否调节高危人群的线粒体功能 MDS干细胞。这将通过研究STAT3与其他蛋白质相互作用的重要性来研究。 线粒体。为了确定这两个角色中的任何一个是否对白血病干细胞的生存至关重要，目标3将 研究靶向IL-6或STAT3是否会降低人类原发MDS患者的植入潜力 免疫缺陷小鼠的样本。基于这些发现，针对STAT3和IL-6的靶向将在体内进行测试 模特们。

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.