Nuclear NAD + homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.

Autor:	Shi X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Jiang Y; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA., Kitano A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Hu T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Murdaugh RL; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA., Li Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA., Hoegenauer KA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Chen R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Takahashi K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Nakada D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. nakada@bcm.edu.; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Jul 21; Vol. 7 (30). Date of Electronic Publication: 2021 Jul 21 (Print Publication: 2021).
DOI:	10.1126/sciadv.abf3895
Abstrakt:	Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD + metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD + biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD + precursors bypassed the dependence of AML on NAMPT but not NMNAT1 , pointing to NMNAT1 as a gatekeeper of NAD + biosynthesis. Deletion of NMNAT1 reduced nuclear NAD + , activated p53, and increased venetoclax sensitivity. Conversely, increased NAD + biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD + for AML progression and chemoresistance. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
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