Defining and targeting the metabolic landscape in Acute Myeloid Leukemia

定义和针对急性髓系白血病的代谢景观

• 批准号: 9806096
• 负责人: Daniela Di Marcantonio
• 金额: $ 10.87万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806096
• 关键词: Acute Myelocytic Leukemia; Address; Biochemistry; Biological Assay; Blood; Cancer Patient; Cell Line; Cells; Cellular Metabolic Process; Chemicals; Complex; Data; Defect; Dependence; Development; Disease Progression; Electron Transport; Ensure; Enzymes; Equilibrium; Expression Profiling; Foundations; Gene Expression; Genetic; Genetically Engineered Mouse; Genus Hippocampus; Gluconeogenesis; Glucose; Glycolysis; Growth; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; In Vitro; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Target; Mus; Mutate; Myelogenous; Outcome; Output; Oxidation-Reduction; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phosphotransferases; Play; Production; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Public Health; Role; Stress Tests; Survival Rate; Technology; Therapeutic; Therapeutic Intervention; Xenograft Model; acute myeloid leukemia cell; base; career; cellular targeting; chemotherapy; comparative; defined contribution; design; effective therapy; enolase; follow-up; glucose uptake; in vivo; inhibitor/antagonist; insight; leukemia treatment; leukemogenesis; liquid chromatography mass spectroscopy; metabolomics; novel; preservation; small hairpin RNA; therapeutic target

PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is an aggressive blood cancer that arises from the aberrant expansion of mutated myeloid-skewed hematopoietic stem and progenitor cells (HSPCs). Given that the current 5-year survival rate for AML patients is below 25%, novel, more effective therapies are desperately needed. Targeting cellular energy production has recently become as a promising point of therapeutic intervention in many cancers including AML. This study aims to uncover the metabolic alterations that support AML pathogenesis and to exploit this information to identify new potential therapeutic targets in AML. We have found that compared to healthy HSPCs, AML cells are more sensitive to perturbations in mitochondria, which are the epicenters of cellular energy. In search of molecular pathways that selectively support metabolism in AML cells but not healthy HSPCs, we recently discovered that the kinase PKCε supports AML survival and progression by preserving redox balance. To gain a deeper understanding of how PKCε does this, we carried out a proteomics analysis and found that PKCε regulates the expression of several mitochondrial and metabolic proteins, including Electron Transport Chain (ETC) complex subunits, transporters, and metabolic enzymes. Follow-up metabolomics analyses in AML cells confirmed that several metabolic pathways, in particular glycolysis and gluconeogenesis, are severely disrupted by PKCε inhibition. A comparative analysis of proteomic and metabolomic data revealed that PKCε regulates multiple enzymatic pinch points within glycolysis. To identify which of the PKCε-regulated glycolytic enzymes may be supporting AML, we performed a retrospective analysis of AML patient gene expression data and observed that increased expression of Enolase (ENO1) is associated with significantly worse AML patient outcomes. Additionally, we found that inhibition of ENO1 activity either genetically or chemically significantly reduces the growth and survival of AML but, of critical importance, not healthy HSPCs. The aims of this proposal are to leverage these observations by: 1) Defining the role of PKCε in AML cellular metabolism; 2) Assessing the therapeutic potential of targeting PKCε-regulated metabolic enzymes, such as ENO1, in AML. The results of this proposal will uncover new metabolic dependences in AML as well as molecular targets that can serve as a basis for developing novel AML therapies. Based on these preliminary data and proposed studies, the central mission of my career plan is to decipher how metabolism influence leukemogenesis and to identify new molecular targets that can be exploited for therapeutic intervention.

项目总结/摘要 急性髓系白血病（AML）是一种侵袭性血癌，其起因于突变型白血病细胞的异常扩增。 骨髓偏斜的造血干细胞和祖细胞（HSPC）。鉴于目前的5年生存率 对于AML患者，低于25%，迫切需要新的，更有效的治疗方法。针对细胞能量 生产最近已成为包括AML在内的许多癌症的治疗干预的一个有希望的点。 这项研究旨在揭示支持AML发病机制的代谢改变，并利用这一点。 信息，以确定新的潜在的治疗靶点在AML。 我们发现，与健康的HSPC相比，AML细胞对线粒体的扰动更敏感， 它们是细胞能量的中心。寻找选择性支持新陈代谢的分子途径 在AML细胞而不是健康的HSPC中，我们最近发现激酶PKCε支持AML存活， 保持氧化还原平衡。为了更深入地了解PKCε是如何做到这一点的，我们进行了 通过蛋白质组学分析，发现PKCε调节多种线粒体和代谢酶的表达， 蛋白质，包括电子传递链（ETC）复合物亚基、转运蛋白和代谢酶。 AML细胞中的后续代谢组学分析证实了几种代谢途径，特别是 糖酵解和糖异生被PKCε抑制严重破坏。蛋白质组学的比较分析 代谢组学数据显示，PKCε调节糖酵解中的多个酶夹点。以识别 PKCε调节的糖酵解酶可能支持AML，我们进行了回顾性分析， AML患者的基因表达数据，并观察到烯醇化酶（ENO 1）表达增加与AML患者的基因表达相关。 AML患者的预后显著更差。此外，我们发现抑制ENO 1活性， 基因或化学显著降低AML的生长和存活，但至关重要的是， 健康的HSPC。本提案的目的是通过以下方式利用这些意见： 1)PKCε在AML细胞代谢中的作用 2)评估AML中靶向PKCε调节的代谢酶（如ENO 1）的治疗潜力。 该提案的结果将揭示AML中新的代谢依赖性以及分子靶点， 可以作为开发新型AML疗法的基础。 基于这些初步的数据和研究建议，我职业规划的中心使命是破译 代谢影响白血病的发生，并确定新的分子靶点，可用于治疗 干预