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加拿大多伦多大学Steven M. Chan研究小组发现，烟酰胺磷酸核苷转移酶抑制剂通过破坏脂质平衡选择性地诱导急性骨髓性白血病（AML）干细胞的凋亡。该项研究成果于2021年7月21日在线发表在《细胞—干细胞》杂志上。

研究人员表示，目前对AML的治疗往往不能有效地消除白血病干细胞（LSC），而这些干细胞使疾病持续存在。

为此，研究人员进行了代谢药物筛选来确定LSC的特异性弱点，并发现烟酰胺磷酸核苷转移酶（NAMPT）抑制剂可选择性地杀死LSC，而不影响正常造血干细胞和祖细胞。用NAMPT抑制剂KPT-9274治疗，抑制了饱和脂肪酸向单不饱和脂肪酸的转化，这一反应由硬脂酰-CoA去饱和酶（SCD）催化，导致了AML细胞的凋亡。用KPT-9274处理的LSC的转录组分析显示，甾醇调节元素结合蛋白（SREBP）调节的基因，包括SCD，对NAMPT抑制剂有部分保护作用。用双嘧达莫抑制SREBP信号增强了KPT-9274对体内LSC的细胞毒性。

这项工作表明，脂质平衡的改变在NAMPT抑制剂诱导的细胞凋亡中起着关键作用，并确定了NAMPT抑制是针对AML中LSC的一种治疗策略。

附：英文原文

Title: Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis

Author: Amit Subedi, Qiang Liu, Dhanoop M. Ayyathan, David Sharon, Severine Cathelin, Mohsen Hosseini, Changjiang Xu, Veronique Voisin, Gary D. Bader, Angelo D’Alessandro, Eric R. Lechman, John E. Dick, Mark D. Minden, Jean C.Y. Wang, Steven M. Chan

Issue&Volume: 2021-07-21

Abstract: Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminatingleukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolicdrug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase(NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stemand progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversionof saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by thestearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomicanalysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-elementbinding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBPsignaling 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-inducedapoptosis and identifies NAMPT inhibition as a therapeutic strategy for targetingLSCs in AML.

DOI: 10.1016/j.stem.2021.06.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00274-5

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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