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Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers

Item Type:Article
Title:Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers
Creators Name:Yusuf, R.Z. and Saez, B. and Sharda, A. and van Gastel, N. and Yu, V.W.C. and Baryawno, N. and Scadden, E.W. and Acharya, S. and Chattophadhyay, S. and Huang, C. and Viswanathan, V. and S'aulis, D. and Cobert, J. and Sykes, D.B. and Keibler, M.A. and Das, S. and Hutchinson, J.N. and Churchill, M. and Mukherjee, S. and Lee, D. and Mercier, F. and Doench, J. and Bullinger, L. and Logan, D.J. and Schreiber, S. and Stephanopoulos, G. and Rizzo, W.B. and Scadden, D.T.
Abstract:Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.
Keywords:Acute Myeloid Leukemia, Aldehyde Oxidoreductases, Aldehydes, Carbolines, Cyclohexylamines, Cytarabine, Doxorubicin, Ferroptosis, Fusion Oncogene Proteins, Hematopoiesis, Inbred C57BL Mice, Knockout Mice, Lipid Peroxidation, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Oleic Acid, Oxidation-Reduction, Oxidative Stress, Phenylenediamines, Phospholipid Hydroperoxide Glutathione Peroxidase, Tumor Cell Line, Animals, Mice
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology
Volume:136
Number:11
Page Range:1303-1316
Date:10 September 2020
Official Publication:https://doi.org/10.1182/blood.2019001808
PubMed:View item in PubMed

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