Targeting mitochondrial dynamics in drug-resistant acute myeloid leukemia

靶向耐药急性髓系白血病的线粒体动力学

• 批准号: 10751235
• 负责人: Christina Glytsou
• 金额: $ 24.9万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-03 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751235
• 关键词: Ablation; Acute Myelocytic Leukemia; Adult; Apoptosis; Apoptotic; Architecture; BCL1 Oncogene; Biochemical; Bioinformatics; Blood; CRISPR interference; CRISPR screen; CRISPR/Cas technology; Caspase; Cell Death Induction; Cell Line; Cells; Clinical; Collaborations; Combined Modality Therapy; Complex Analysis; Crista ampullaris; Data; Development Plans; Drug resistance; Electron Microscopy; Ensure; Equipment; Event; Genes; Genetic; Goals; Growth; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; In Vitro; Induction of Apoptosis; Laboratories; Lead; Malignant Neoplasms; Mediating; Mentors; Microscopy; Mitochondria; Molecular; Morphology; OPA1 gene; Organelles; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Physiological; Process; Prognosis; Proteins; Proteolysis; Proteolytic Processing; Regulation; Research; Research Personnel; Resistance; Resistance development; Resources; Role; Sampling; Scientist; Shapes; Stress; Structure; Survival Rate; System; Techniques; Testing; Therapeutic; Training; United States Food and Drug Administration; Xenograft procedure; acquired drug resistance; acute myeloid leukemia cell; cancer cell; career development; chaperonin; course development; cytochrome c; drug resistance development; efficacy evaluation; electron tomography; experimental study; genome-wide; in vivo; inhibitor; innovation; leukemia; mimetics; mitochondrial dysfunction; mortality; mouse model; novel; pharmacologic; post-doctoral training; pre-clinical; prevent; programs; protein complex; research and development; response; skills; small molecule; spatiotemporal; success; superresolution imaging; superresolution microscopy; targeted treatment; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is the second most common leukemia in adults and typically has a dismal prognosis and high mortality, which is exemplified by a 28% five-year overall survival rate. Venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, has received FDA approval for the treatment of AML. Despite promising early responses of AML patients to venetoclax, drug resistance ensues after prolonged treatment and highlights the urgency for a deep understanding of the underlying mechanisms. Recently, I discovered that mitochondria in AML cells undergo a morphological change upon venetoclax resistance. Using a genome-wide CRISPRi screen in human AML, I identified genes involved in mitochondrial structure as synthetic lethal vulnerabilities for venetoclax in AML. Mitochondria of venetoclax-resistant AML cells actively modify their architecture and function to prevent apoptosis. Supporting this, OPA1, the master regulator of mitochondrial cristae structure, and CLPB, a mitochondrial chaperonin, were strikingly upregulated in venetoclax-resistant AML cells relative to the sensitive cells. CLPB directly interacts with OPA1 to maintain the physiological mitochondrial morphology. Promisingly, genetic CLPB or OPA1 ablation enhances venetoclax-induced apoptosis of AML cells, by promoting cristae remodeling and mitochondrial stress. This proposal aims to leverage these observations by 1) delineating the mechanistic details by which mitochondrial dynamics and homeostasis lead to acquisition of drug resistance in AML, using super-resolution microscopy, electron tomography, and biochemical techniques, and 2) assessing the therapeutic potential of perturbing mitochondrial structure to augment venetoclax action in preclinical AML mouse models. This research stands to have significant clinical impact, because it can serve as a basis for developing new combinational targeted therapies for patients with AML. In addition, this proposal outlines my career development plan for obtaining the requisite training to transition into a successful independent investigator. This includes 1) guidance from my esteemed mentor Dr. Iannis Aifantis, expert in blood malignancies and mouse models; 2) scientific training by an expert advisory panel, consisting of Drs. Raoul Tibes, Hans-Willem Snoeck, Kivanc Birsoy and Evripidis Gavathiotis, all in top institutes of NYC; 3) hands-on training using state-of-art equipment, including super-resolution microscopy with Dr. Eli Rothenberg; 4) collaboration with experts in microscopy and bioinformatics; and 5) career development courses sponsored by NYU. The laboratory of Dr. Aifantis and NYU Department of Pathology will provide the resources critical to my training and research, ensuring my success. This extensive professional growth program will guide me during the mentored phase excelling as an independent academic scientist. Collectively, the proposed research and career development plans are expected to generate data with significant impact on circumventing targeted-therapy resistance in AML and setting the basis of my future research as an independent researcher.

项目总结/摘要 急性髓性白血病（AML）是成人中第二常见的白血病，通常具有令人沮丧的预后。 预后差，死亡率高，五年总生存率为28%。维奈托克，选择性 抗凋亡蛋白BCL-2的抑制剂，已获得FDA批准用于治疗AML。尽管 AML患者对维奈托克有希望的早期反应，长期治疗后耐药性增强， 强调了深入了解基本机制的紧迫性。最近，我发现， AML细胞中的线粒体在维奈托克抗性时经历形态学变化。使用全基因组 CRISPRi在人类AML中的筛选，我将参与线粒体结构的基因鉴定为合成致死基因 维奈托克在AML中的漏洞维奈托克耐药AML细胞的线粒体主动修饰其 防止细胞凋亡的结构和功能。支持这一点，OPA 1，线粒体的主要调节因子， 嵴结构和CLPB，一种线粒体伴侣蛋白，在维奈托克耐药AML中显著上调 相对于敏感细胞。CLPB直接与OPA 1相互作用以维持生理性线粒体 形态学有希望的是，基因CLPB或OPA 1消融增强了维奈托克诱导的AML细胞凋亡， 通过促进嵴重塑和线粒体压力。 该提案旨在通过以下方式利用这些观察结果：1）描绘机械细节， 线粒体动力学和稳态导致AML获得耐药性，使用超分辨率 显微镜、电子断层扫描和生物化学技术，以及2）评估 扰乱线粒体结构以增强维奈托克在临床前AML小鼠模型中的作用。本研究 具有重大的临床影响，因为它可以作为开发新的组合药物的基础。 AML患者的靶向治疗。 此外，本提议概述了我的职业发展计划，以获得过渡所需的培训 成功的独立调查员这包括我尊敬的导师伊安尼斯博士的指导 Aifantis，血液恶性肿瘤和小鼠模型专家; 2）专家咨询小组的科学培训， 由拉乌尔·提贝斯博士、汉斯-威廉·斯诺克博士、基万茨·比尔索伊博士和埃夫里普·加瓦蒂奥蒂斯博士组成，他们都在顶级研究所工作。 3）使用最先进的设备进行实践培训，包括Eli博士的超分辨率显微镜 Rothenberg; 4）与显微镜和生物信息学专家合作; 5）职业发展课程 由NYU赞助。Aifantis博士的实验室和纽约大学病理学系将提供资源 这对我的训练和研究至关重要，确保了我的成功。这一广泛的专业成长计划将指导 我在指导阶段擅长作为一个独立的学术科学家。总体而言，拟议的 研究和职业发展计划预计将产生数据，对规避 AML的靶向治疗耐药性，并为我未来作为独立研究人员的研究奠定基础。