Subedi Amit, Liu Qiang, Ayyathan Dhanoop M, Sharon David, Cathelin Severine, Hosseini Mohsen, Xu Changjiang, Voisin Veronique, Bader Gary D, D'Alessandro Angelo, Lechman Eric R, Dick John E, Minden Mark D, Wang Jean C Y, Chan Steven M
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada.
Cell Stem Cell. 2021 Oct 7;28(10):1851-1867.e8. doi: 10.1016/j.stem.2021.06.004. Epub 2021 Jul 21.
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.
目前用于治疗急性髓系白血病（AML）的方法往往无法有效清除白血病干细胞（LSC），而正是这些细胞导致了疾病的持续存在。在此，我们进行了一项代谢药物筛选以确定LSC特有的弱点，发现烟酰胺磷酸核糖转移酶（NAMPT）抑制剂能选择性杀死LSC，同时使正常造血干细胞和祖细胞免受影响。使用NAMPT抑制剂KPT-9274进行治疗，可抑制饱和脂肪酸向单不饱和脂肪酸的转化，这一反应由硬脂酰辅酶A去饱和酶（SCD）催化，从而导致AML细胞凋亡。对用KPT-9274处理的LSC进行转录组分析发现，固醇调节元件结合蛋白（SREBP）调控的基因上调，包括SCD，这赋予了对NAMPT抑制剂的部分保护作用。用双嘧达莫抑制SREBP信号增强了KPT-9274在体内对LSC的细胞毒性。我们的研究表明，脂质稳态的改变在NAMPT抑制剂诱导的细胞凋亡中起关键作用，并确定抑制NAMPT是靶向AML中LSC的一种治疗策略。
