Mitochondrial NAD+ in Acute Myeloid Leukemias

急性髓系白血病中的线粒体 NAD

基本信息

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
项目类别：
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

项目摘要

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样白血病（AML）研究的活跃领域。累积数据表明AML细胞已经增强了线粒体活性，并且更喜欢谷氨酰胺作为一种与非癌细胞相比，碳源。然而，试图针对目标时出现的挑战这些脆弱性一次是持续存在治疗 - fractrantary AML细胞，最终导致复发或发展的抗性。可能的原因是代谢途径的适应性以及由于局部环境或遗传学而导致的细胞间变异性。我们建议线粒体烟酰胺腺苷二核苷酸（NAD+）的损失将同时阻止AML在健康细胞中使用的多种代谢途径。我们最近出版了 SLC25A51转运蛋白是人类细胞中线粒体NAD+水平的关键调节剂。 SLC25A51是直接负责NAD+进口，SLC25A51表达的调制控制着浓度线粒体基质中的NAD+。 SLC25A51的损失仅导致NAD+仅在线粒体中而不是在整个细胞中。到目前为止，一直无法选择性地耗尽线粒体NAD+ 内源性目标。值得注意的是，我们发现在AML细胞之间存在广泛的脆弱性，可耗尽SLC25A51耗竭，包括以前被发现可以避免复杂I抑制的线。该建议将确定SLC25A51影响AML体内的程度，阐明途径该转运蛋白支持并确定控制其表达的分子机制。如有患者的治疗方案有限，这项工作的长期利益是建立针对目标的理由线粒体NAD+通过SLC25A51并识别其他AML治疗方法。