Alterations in fatty acid metabolism in the pathogenesis of leukemic stem cells from Acute Myeloid Leukemia patients

急性髓系白血病患者白血病干细胞发病机制中脂肪酸代谢的改变

• 批准号: 10404634
• 负责人: Rachel Culp-Hill
• 金额: $ 2.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404634
• 关键词: Acute Myelocytic Leukemia; Amino Acids; Apoptotic; Automobile Driving; Bone Marrow Cells; Clinical Research; Data; Development; Disease; Disease Progression; Drops; Fatty Acid Desaturases; Fatty Acids; Foundations; Future; Genetic; Goals; Hematopoietic stem cells; Lead; Link; Lipids; Malignant Bone Neoplasm; Metabolic; Metabolism; Methods; Myelogenous; Oxidative Phosphorylation; Oxides; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Production; Prognosis; Refractory; Regulation; Relapse; Research Design; Role; TP53 gene; Unsaturated Fats; Unsaturated Fatty Acids; Up-Regulation; acute myeloid leukemia cell; amino acid metabolism; chemotherapy; conventional therapy; experimental study; fatty acid metabolism; fatty acid oxidation; improved; insight; leukemia; leukemic stem cell; lipid metabolism; metabolomics; neoplastic cell; novel; novel strategies; novel therapeutic intervention; oxidation; prevent; progenitor; relapse patients; stem cell survival; treatment strategy

PROJECT ABSTRACT Acute myeloid leukemia (AML) is a cancer of bone marrow-derived blood cells, where leukemic blasts build up and block proper function and development of myeloid progenitors. Conventional therapy eliminates most bulk tumor cells but disease-initiating leukemic stem cells (LSCs) survive, leading to disease progression and relapse2. Unlike bulk tumor cells and normal hematopoietic stem cells, LSCs rely on oxidative phosphorylation (OXPHOS). Thus, targeting OXPHOS is a promising strategy to selectively eradicate LSCs. The key metabolic drivers of OXPHOS in LSCs from relapsed patients are amino acid and fatty acid metabolism7. While we have previously described successful strategies for targeting amino acid metabolism8 the mechanisms that control fatty acid metabolism remain to be elucidated. Thus, the primary objective of this proposal is to better understand how fatty acids are metabolized to fuel OXPHOS in LSCs. LSCs in relapsed/refractory patients display increased fatty acid metabolism, which drives OXPHOS and LSC survival. We also show a strong correlation between fatty acid desaturase (FADS) expression and poor prognosis in AML. As unsaturated fatty acids are oxidized more rapidly than saturated9, increased FADS activity fuels OXPHOS even more than overall fatty acid metabolism. This suggests pharmacological targeting of fatty acid desaturation may offer a novel approach for LSC eradication in relapsed/refractory AML patients. We have also shown similar increases in fatty acid desaturation in cases of p53 loss in AML. Successful inhibition of OXPHOS is dependent on p53-driven apoptotic pathways, and p53 is a tight regulator of lipid metabolism. Therefore, a loss of p53 in AML may result in a loss of FADS inhibition and promotion of fatty acid desaturation. Increased unsaturated fatty acids may also drive inactivation of p53, resulting in further lipid aberrations. We hypothesize that relapsed/refractory LSCs upregulate fatty acid desaturation through increased FADS activity to maintain OXPHOS as a mechanism for survival. Our goal is to determine the mechanism by which relapsed/refractory LSCs maintain OXPHOS through fatty acid oxidation. Due to evidence linking loss of p53 and increased fatty acid desaturation, we also hypothesize that loss of p53 function in relapsed/refractory LSCs results in loss of inhibition of FADS1, increasing fatty acid desaturation. As increased unsaturated lipids modify p53 activity, this may drive continued p53 inactivation resulting in further lipid aberrations. These studies will determine whether inhibition of FADS1 prevents production of unsaturated fatty acids in relapsed/refractory LSCs, leading to novel therapeutic strategies. Together, the experiments described in this proposal will offer novel insights into the metabolism of relapsed/refractory LSCs and lay the groundwork for future clinical studies designed to better eradicate LSCs in AML patients.

项目摘要 急性髓样白血病（AML）是骨髓衍生的血细胞的癌，白血病爆炸 建立并阻止正确的功能和髓样祖细胞的发展。常规疗法消除 大多数散装肿瘤细胞但引发疾病的白血病干细胞（LSC）生存，导致疾病进展 和复发2。与散装肿瘤细胞和正常造血干细胞不同，LSC依赖于氧化 磷酸化（OXPHOS）。因此，靶向OXPHOS是选择性根除LSC的有前途的策略。这 来自复发患者LSC的OXPHOS的主要代谢驱动因素是氨基酸和脂肪酸代谢7。 虽然我们先前已经描述了靶向氨基酸代谢的成功策略8机制 控制脂肪酸代谢仍有待阐明。因此，该提议的主要目的是改善 了解如何将脂肪酸代谢为LSC中的Oxphos。 复发/难治性患者的LSC表现出增加的脂肪酸代谢，驱动Oxphos和 LSC生存。我们还显示出脂肪酸去饱和酶（FADS）表达和较差之间的密切相关性 AML的预后。由于不饱和脂肪酸比饱和9更快地氧化了，因此FADS活性增加 燃料比整体脂肪酸代谢还要多。这表明脂肪的药理靶向 酸性去饱和可能为复发/难治性AML患者的LSC根除提供了一种新颖的方法。我们有 在AML中p53损失的情况下，脂肪酸去饱和的同样增加。成功抑制 Oxphos取决于p53驱动的凋亡途径，p53是脂质代谢的紧密调节剂。 因此，AML中p53的损失可能导致FAD抑制和促进脂肪酸去饱和度的损失。 不饱和脂肪酸增加也可能驱动p53失活，从而导致进一步的脂像差。 我们假设复发/难治性LSC通过增加而上调脂肪酸的饱和度 流行的活性以维持oxphos作为生存机制。我们的目标是通过 复发/难治性LSC通过脂肪酸氧化维持Oxphos。由于证据联系了损失 p53和增加的脂肪酸去饱和，我们还假设p53功能在复发/难治性中的丧失 LSC会导致FADS1抑制作用丧失，从而增加脂肪酸的去饱和度。随着不饱和脂质的增加 修改p53活性，这可能会驱动持续的p53失活，从而导致进一步的脂像差。这些研究 将确定抑制FADS1是否可以防止复发/难治性中不饱和脂肪酸的产生 LSC，导致新颖的治疗策略。一起，本提案中描述的实验将提供 对复发/难治性LSC的代谢的新见解，并为将来的临床研究奠定了基础 旨在更好地消除AML患者的LSC。

项目成果

Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.

• DOI: 10.3390/metabo13040467
• 发表时间: 2023-03-24
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Culp-Hill R;Stevens BM;Jones CL;Pei S;Dzieciatkowska M;Minhajuddin M;Jordan CT;D'Alessandro A
• 通讯作者: D'Alessandro A