急性髓系白血病 (AML) 是一种毁灭性疾病，由称为白血病干细胞 (LSC) 的罕见细胞亚群引发和维持。 LSC 负责推动疾病复发，因此迫切需要开发针对 LSC 的新治疗策略。使用基于质谱的代谢组学分析能够发现 LSC 中独特且可靶向的代谢特性。然而，我们对 LSC 与其正常对应物、造血干细胞和祖细胞 (HSPC) 之间的代谢差异还没有全面的了解。在这项研究中，我们使用基于质谱的无偏代谢组学分析来定义原代人类 LSC 和 HSPC 之间代谢物的差异，这表明 LSC 具有独特的代谢组。与 HSPC 相比，亚精胺是 LSC 中最丰富的代谢物。亚精胺浓度的药理降低会降低 LSC 功能，但不会影响正常 HSPC。多胺消耗还减少了患者来源的异种移植物中的白血病负担。从机制上讲，亚精胺消耗通过减少 eIF5A 依赖性蛋白质合成来诱导 LSC 骨髓分化，从而导致选定的蛋白质子集表达减少。 KAT7 是一种组蛋白乙酰转移酶，是被确定会因亚精胺耗尽而下调的最重要候选酶之一。 KAT7 的过度表达部分挽救了多胺耗竭引起的集落形成能力下降，表明 KAT7 的缺失是亚精胺耗竭靶向 AML 克隆形成潜力的机制的重要组成部分。我们共同发现并从机制上剖析了 LSC 的代谢脆弱性，该脆弱性有可能快速转化为临床试验，以改善 AML 患者的预后。

Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry-based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion-induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML.