SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

Autor:	Yan D; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Franzini A; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Pomicter AD; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Halverson BJ; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Antelope O; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Mason CC; Department of Pediatrics, University of Utah, Salt Lake City, Utah., Ahmann JM; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Senina AV; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Vellore NA; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Jones CL; Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Zabriskie MS; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Than H; Department of Haematology, Singapore General Hospital, Singapore., Xiao MJ; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., van Scoyk A; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Patel AB; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, Utah., Clair PM; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Heaton WL; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Owen SC; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah., Andersen JL; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah., Egbert CM; Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah., Reisz JA; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado., D'Alessandro A; Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Cox JE; Department of Biochemistry, University of Utah, Salt Lake City, Utah., Gantz KC; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Redwine HM; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Iyer SM; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Khorashad JS; Department of Immunology and Inflammation, Imperial College London, London, United Kingdom., Rajabi N; Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Olsen CA; Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., O'Hare T; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, Utah., Deininger MW; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. Michael.Deininger@hci.utah.edu.; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, Utah.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2021 May; Vol. 2 (3), pp. 266-287. Date of Electronic Publication: 2019 Dec 02.
DOI:	10.1158/2643-3230.BCD-20-0168
Abstrakt:	We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. Competing Interests: COMPETING INTERESTS STATEMENT Michael W. Deininger reports research funding and paid advisory board membership for the following companies: Blueprint, Pfizer, Novartis, Takeda, Incyte, Fusion Pharma, Medscape and Ascentage Pharma. None of these relationships pose any conflict of interest with the present manuscript. The other authors report no competing interests.
Databáze:	MEDLINE
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