Mitochondrial NAD+ in Acute Myeloid Leukemias

急性髓系白血病中的线粒体 NAD

• 批准号: 10655208
• 负责人: Xiaolu Ang Cambronne
• 金额: $ 52.25万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655208
• 关键词: Acute Myelocytic Leukemia; Adjuvant; Affect; Apoptosis; Area; Binding; Binding Sites; Biosensor; Bone Marrow Transplantation; Carbon; Cell Line; Cells; ChIP-seq; Citric Acid Cycle; Clinical; Complex; Consumption; Cytoplasm; Data; Data Set; Deoxyribonucleases; Dependence; Disease; Disease model; Environment; Genetic; Glutaminase; Glutamine; Hematopoietic stem cells; Human; Hypersensitivity; Immunotherapy; Individual; Malate-Aspartate Shuttle Pathway; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Molecular; Mutate; Myelosuppression; Nature; Nicotinamide adenine dinucleotide; Oxidative Phosphorylation; Pathway interactions; Patients; Phenotype; Production; Proliferating; Proteins; Publishing; Recurrent disease; Refractory; Regulation; Relapse; Research; Resistance development; Role; Sampling; Source; Specimen; Supplementation; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Tumor Burden; Tumor Promotion; Work; Xenograft procedure; acute myeloid leukemia cell; addiction; age group; aging population; c-myc Genes; chemotherapy; chemotherapy induced neuropathy; combinatorial; deprivation; fitness; human old age (65+); in vivo; inhibitor; metabolomics; mitochondrial metabolism; mortality; mouse model; older patient; promoter; therapeutic target; trait; tumor metabolism; tumorigenesis

PROJECT SUMMARY Targeting mitochondrial metabolism is an active area of research in Acute Myeloid Leukemia (AML). The cumulative data indicate that AML cells have heightened mitochondrial activity and prefer glutamine as a carbon source compared to noncancerous cells. Nevertheless, a challenge that emerges when trying to target these vulnerabilities one at a time is the continued presence of treatment-refractory AML cells, which ultimately result in relapse or developed resistance. The likely causes are the adaptable nature of metabolic pathways and cell-to-cell variability, either due to local environment or genetics. We propose that loss of mitochondrial nicotinamide adenine dinucleotide (NAD+) will simultaneously block multiple metabolic pathways used by AML with minimal toxicity in healthy cells. We recently published that the SLC25A51 transporter is a critical regulator of mitochondrial NAD+ levels in human cells. SLC25A51 is directly responsible for NAD+ import, and modulation of SLC25A51 expression controls the concentrations of NAD+ in the mitochondrial matrix. Loss of SLC25A51 resulted in depleted NAD+ only in mitochondria and not throughout the whole cell. Until now, there has been no way to selectively deplete mitochondrial NAD+ through an endogenous target. Notably, we have found a broad vulnerability across AML cells to SLC25A51 depletion, including lines that previously were found to escape Complex I inhibition. This proposal will determine the extent that SLC25A51 impacts AML in vivo, elucidate the pathways that this transporter supports, and determine the molecular mechanisms controlling its expression. As there are limited treatment options for patients, the long-term benefit of this work is to establish a rationale for targeting mitochondrial NAD+ through SLC25A51 and to identify additional AML therapeutic approaches.

项目摘要 靶向线粒体代谢是急性髓系白血病（AML）的一个活跃研究领域。 累积数据表明，AML细胞的线粒体活性增强，并且更喜欢谷氨酰胺作为治疗药物。 与非癌细胞相比，然而，当试图瞄准 这些脆弱性一次一个是治疗难治性AML细胞的持续存在，最终 导致复发或产生耐药性。可能的原因是代谢途径的适应性 以及细胞与细胞之间的变异性，无论是由于局部环境还是遗传。 我们认为，线粒体的烟酰胺腺嘌呤二核苷酸（NAD+）的损失将同时 阻断AML使用的多种代谢途径，对健康细胞的毒性最小。我们最近发表 SLC25A51转运蛋白是人类细胞中线粒体NAD+水平的关键调节因子。SLC25A51是 直接负责NAD+的输入，而SLC25A51表达的调节控制了 线粒体基质中的NAD+。SLC25A51的缺失仅导致线粒体中NAD+的耗尽，而不导致线粒体中NAD+的缺失。 整个细胞。到目前为止，还没有办法通过选择性地消耗线粒体NAD+， 内源性靶点。值得注意的是，我们已经发现AML细胞对SLC25A51耗尽的广泛脆弱性， 包括先前发现逃避复合体I抑制的细胞系。 该提案将确定SLC25A51在体内影响AML的程度，阐明其途径， 这种转运蛋白支持，并确定控制其表达的分子机制。因为有 由于患者的治疗选择有限，这项工作的长期益处是建立靶向治疗的基本原理。 通过SLC25A51研究线粒体NAD+，并确定其他AML治疗方法。