We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.

我们之前证明了白血病干细胞 (LSC)从头急性髓系白血病 (AML) 患者选择性地依赖于氨基酸代谢，而 venetoclax 和阿扎胞苷 (ven/aza) 联合治疗会抑制氨基酸代谢，导致细胞死亡。相比之下，ven/aza 未能根除复发/难治性 (R/R) 患者的 LSC，表明代谢特性发生了改变。详细的代谢组学分析显示，复发性 LSCs 中烟酰胺代谢升高，这会激活氨基酸代谢和脂肪酸氧化以驱动 OXPHOS，从而为 LSCs 规避 ven/aza 治疗的细胞毒性作用提供了一种手段。烟酰胺磷酸核糖基转移酶 (NAMPT) 的遗传和药理学抑制，烟酰胺代谢中的限速酶，证明选择性根除 R/R LSC，同时保留正常的造血干/祖细胞。总之，这些发现表明烟酰胺代谢升高既是 ven/aza 抗性的机制基础，也是 R/R LSC 的代谢脆弱性。