| Literature DB >> 32458004 |
Rushdia Zareen Yusuf1,2,3, Borja Saez1,2,3, Azeem Sharda1,2,3, Nick van Gastel1,2,3, Vionnie W C Yu1,2,3, Ninib Baryawno1,2,3, Elizabeth W Scadden1,2,3, Sanket Acharya1,2,3, Shrikanta Chattophadhyay4, Cherrie Huang4, Vasanthi Viswanathan4, Dana S'aulis5, Julien Cobert1,2,3, David B Sykes1,2,3, Mark A Keibler6, Sudeshna Das7, John N Hutchinson8, Michael Churchill1,2,3, Siddhartha Mukherjee1,2,3, Dongjun Lee1,2,3, Francois Mercier1,2,3, John Doench4, Lars Bullinger9, David J Logan4, Stuart Schreiber4, Gregory Stephanopoulos6, William B Rizzo5, David T Scadden1,2,3.
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.Entities:
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Year: 2020 PMID： 32458004 PMCID： PMC7483435 DOI： 10.1182/blood.2019001808
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 25.476