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

Blood. 2020 Sep 10;136(11):1303-1316. doi: 10.1182/blood.2019001808.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Oxidoreductases / genetics
  • Aldehyde Oxidoreductases / physiology*
  • Aldehydes / pharmacology
  • Animals
  • Carbolines / pharmacology*
  • Cell Line, Tumor
  • Cyclohexylamines / pharmacology*
  • Cytarabine / administration & dosage
  • Doxorubicin / administration & dosage
  • Ferroptosis / drug effects*
  • Hematopoiesis / physiology*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / pathology
  • Lipid Peroxidation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Oleic Acid / pharmacology
  • Oncogene Proteins, Fusion / physiology
  • Oxidation-Reduction
  • Oxidative Stress
  • Phenylenediamines / pharmacology*
  • Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors
  • Phospholipid Hydroperoxide Glutathione Peroxidase / physiology


  • Aldehydes
  • Carbolines
  • Cyclohexylamines
  • MLL-AF9 fusion protein, human
  • MLL-AF9 fusion protein, mouse
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Phenylenediamines
  • RSL3 compound
  • ferrostatin-1
  • Cytarabine
  • Myeloid-Lymphoid Leukemia Protein
  • Oleic Acid
  • Doxorubicin
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • Aldehyde Oxidoreductases
  • long-chain-aldehyde dehydrogenase
  • 4-hydroxy-2-nonenal