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Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
- Source :
-
Cell stem cell [Cell Stem Cell] 2021 Oct 07; Vol. 28 (10), pp. 1851-1867.e8. Date of Electronic Publication: 2021 Jul 21. - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1875-9777
- Volume :
- 28
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell stem cell
- Publication Type :
- Academic Journal
- Accession number :
- 34293334
- Full Text :
- https://doi.org/10.1016/j.stem.2021.06.004