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

项目摘要 急性髓性白血病（AML）是一种骨髓源性血细胞的癌症，其中白血病母细胞 建立并阻断骨髓祖细胞的正常功能和发育。常规治疗消除了 大多数大块肿瘤细胞，但引发疾病的白血病干细胞（LSC）存活，导致疾病进展 复发2。与大量肿瘤细胞和正常造血干细胞不同，LSC依赖于氧化应激。 磷酸化（OXPHOS）。因此，靶向OXPHOS是选择性根除LSC的一种有希望的策略。的 来自复发患者的LSC中OXPHOS的关键代谢驱动因素是氨基酸和脂肪酸代谢7。 虽然我们先前描述了靶向氨基酸代谢的成功策略8， 控制脂肪酸代谢的蛋白质仍有待阐明。因此，这项建议的主要目的是更好地 了解脂肪酸如何代谢为LSC中的OXPHOS提供燃料。 复发性/难治性患者中的LSC显示出增加的脂肪酸代谢，其驱动OXPHOS和 LSC存活率。我们还发现脂肪酸去饱和酶（FADS）表达与低表达之间有很强的相关性。 AML的预后。由于不饱和脂肪酸的氧化速度比饱和脂肪酸快9， OXPHOS的能量甚至超过整个脂肪酸代谢。这表明药理学靶向脂肪 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丢失的情况下也显示脂肪酸去饱和的类似增加。成功抑制 OXPHOS依赖于p53驱动的凋亡途径，并且p53是脂质代谢的严格调节剂。 因此，AML中p53的缺失可能导致FADS抑制的缺失和脂肪酸去饱和的促进。 增加的不饱和脂肪酸也可能驱动p53的失活，导致进一步的脂质畸变。 我们假设复发性/难治性LSC通过增加脂肪酸饱和度来上调脂肪酸去饱和， 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： 复发性/难治性LSC通过脂肪酸氧化维持OXPHOS。由于有证据表明， p53和脂肪酸去饱和增加，我们还假设复发性/难治性乳腺癌中p53功能丧失， LSC导致FADS 1抑制作用丧失，增加脂肪酸去饱和。由于不饱和脂质增加 改变p53活性，这可能驱动p53持续失活，导致进一步的脂质畸变。这些研究 将确定FADS 1的抑制是否阻止复发性/难治性中不饱和脂肪酸的产生。 LSC，导致新的治疗策略。总之，本提案中描述的实验将提供 对复发/难治性LSC的代谢有了新的认识，并为未来的临床研究奠定了基础 旨在更好地根除AML患者中的LSC。

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.