Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA.
Division of Hematology, University of Colorado Denver, Aurora, CO 80045, USA.
Cell Stem Cell. 2020 Nov 5;27(5):748-764.e4. doi: 10.1016/j.stem.2020.07.021. Epub 2020 Aug 20.
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.
我们之前的研究表明，初发急性髓系白血病（AML）患者中的白血病干细胞（LSCs）对氨基酸代谢具有选择性依赖性，而 venetoclax 和阿扎胞苷（ven/aza）联合治疗可抑制氨基酸代谢，导致细胞死亡。相比之下，ven/aza 在复发性/难治性（R/R）患者中无法根除 LSCs，这表明代谢特性发生了改变。详细的代谢组学分析显示，复发 LSCs 中的烟酰胺代谢升高，这激活了氨基酸代谢和脂肪酸氧化，从而驱动 OXPHOS，为 LSCs 提供了一种规避 ven/aza 治疗细胞毒性的手段。烟酰胺磷酸核糖转移酶（NAMPT）是烟酰胺代谢的限速酶，对其进行遗传和药理学抑制，可选择性地根除 R/R LSCs，同时保留正常造血干/祖细胞。总的来说，这些发现表明，升高的烟酰胺代谢既是 ven/aza 耐药的机制基础，也是 R/R LSCs 的代谢脆弱性。
