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

Rushdia Zareen Yusuf, Borja Saez, Azeem Sharda, Nick van Gastel, Vionnie W.C. Yu, Ninib Baryawno, Elizabeth W. Scadden, Sanket Acharya, Shrikanta Chattophadhyay, Cherrie Huang, Vasanthi Viswanathan, Dana S'aulis, Julien Cobert, David B. Sykes, Mark A. Keibler, Sudeshna Das, John N. Hutchinson, Michael Churchill, Siddhartha Mukherjee, Dongjun LeeFrancois Mercier, John Doench, Lars Bullinger, David J. Logan, Stuart Schreiber, Gregory Stephanopoulos, William B. Rizzo, David T. Scadden

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1303-1316
Number of pages14
JournalBlood
Volume136
Issue number11
DOIs
StatePublished - Sep 10 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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