Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.

目前对急性髓性白血病 (AML) 的治疗在消除白血病干细胞 (LSC) 方面通常是无效的，这会使该疾病持续存在。在这里，我们进行了代谢药物筛选以识别 LSC 特异性漏洞，发现烟酰胺磷酸核糖基转移酶 (NAMPT) 抑制剂选择性地杀死 LSC，同时保留正常的造血干细胞和祖细胞。用 NAMPT 抑制剂 KPT-9274 处理可抑制饱和脂肪酸向单不饱和脂肪酸的转化，这是由硬脂酰辅酶 A 去饱和酶 (SCD) 催化的反应，导致 AML 细胞凋亡。用 KPT-9274 处理的 LSC 的转录组学分析揭示了甾醇调节元件结合蛋白 (SREBP) 调节基因的上调，包括SCD、这赋予了对 NAMPT 抑制剂的部分保护。用双嘧达莫抑制 SREBP 信号增强了 KPT-9274在体内对 LSCs 的细胞毒性。我们的工作表明改变的脂质稳态在 NAMPT 抑制剂诱导的细胞凋亡中起关键作用，并将 NAMPT 抑制确定为针对 AML 中 LSCs 的治疗策略。