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 急性髓系白血病 (AML) 是一种骨髓来源的血细胞癌症，其中白血病母细胞 建立并阻止骨髓祖细胞的正常功能和发育。传统疗法可消除 大多数肿瘤细胞但疾病引发的白血病干细胞 (LSC) 存活下来，导致疾病进展 和复发2。与大量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，针对 OXPHOS 是选择性根除 LSC 的一种有前景的策略。这 复发患者 LSC 中 OXPHOS 的关键代谢驱动因素是氨基酸和脂肪酸代谢7。 虽然我们之前描述了针对氨基酸代谢的成功策略8，但其机制 控制脂肪酸代谢的机制仍有待阐明。因此，本提案的主要目标是更好地 了解脂肪酸如何代谢以在 LSC 中为 OXPHOS 提供燃料。 复发/难治性患者的 LSC 表现出脂肪酸代谢增加，从而驱动 OXPHOS 和 LSC 存活率。我们还表明脂肪酸去饱和酶（FADS）表达与不良反应之间存在很强的相关性。 AML 的预后。由于不饱和脂肪酸比饱和脂肪酸氧化得更快，因此 FADS 活性增加 对 OXPHOS 的促进作用甚至超过了整体脂肪酸代谢。这表明脂肪的药理学靶向 酸去饱和可能为复发/难治性 AML 患者的 LSC 根除提供一种新方法。我们有 在 AML 中 p53 缺失的情况下，脂肪酸去饱和度也显示出类似的增加。成功抑制 OXPHOS 依赖于 p53 驱动的细胞凋亡途径，而 p53 是脂质代谢的严格调节因子。 因此，AML 中 p53 的缺失可能导致 FADS 抑制作用的丧失和脂肪酸去饱和的促进。 不饱和脂肪酸的增加也可能导致 p53 失活，导致进一步的脂质畸变。 我们假设复发/难治性 LSC 通过增加脂肪酸去饱和度来上调脂肪酸去饱和度。 FADS 活性维持 OXPHOS 作为生存机制。我们的目标是通过以下方式确定机制： 复发/难治性 LSC 通过脂肪酸氧化维持 OXPHOS。由于有证据表明损失 p53 和脂肪酸去饱和度增加，我们还假设复发/难治性患者中 p53 功能的丧失 LSC 导致 FADS1 的抑制作用丧失，从而增加脂肪酸去饱和度。随着不饱和脂质的增加 改变 p53 活性，这可能会驱动 p53 持续失活，导致进一步的脂质畸变。这些研究 将确定抑制 FADS1 是否可以阻止复发/难治性患者不饱和脂肪酸的产生 LSCs，带来新的治疗策略。总之，本提案中描述的实验将提供 对复发/难治性 LSC 代谢的新见解，为未来的临床研究奠定基础 旨在更好地根除 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