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 Lee; Francois Mercier; John Doench; Lars Bullinger; David J Logan; Stuart Schreiber; Gregory Stephanopoulos; William B Rizzo; David T Scadden

doi:10.1182/blood.2019001808

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.

Authors

Rushdia Zareen Yusuf^{1

2

3}, Borja Saez^{1

2

3}, Azeem Sharda^{1

2

3}, Nick van Gastel^{1

2

3}, Vionnie W C Yu^{1

2

3}, Ninib Baryawno^{1

2

3}, Elizabeth W Scadden^{1

2

3}, Sanket Acharya^{1

2

3}, Shrikanta Chattophadhyay⁴, Cherrie Huang⁴, Vasanthi Viswanathan⁴, Dana S'aulis⁵, Julien Cobert^{1

2

3}, David B Sykes^{1

2

3}, Mark A Keibler⁶, Sudeshna Das⁷, John N Hutchinson⁸, Michael Churchill^{1

2

3}, Siddhartha Mukherjee^{1

2

3}, Dongjun Lee^{1

2

3}, Francois Mercier^{1

2

3}, John Doench⁴, Lars Bullinger⁹, David J Logan⁴, Stuart Schreiber⁴, Gregory Stephanopoulos⁶, William B Rizzo⁵, David T Scadden^{1

2

3}

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.
² Department of Stem Cell and Regenerative Biology and.
³ Harvard Stem Cell Institute, Harvard University, Cambridge, MA.
⁴ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA.
⁵ Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE.
⁶ Department of Chemical Engineering, MIT, Cambridge, MA.
⁷ Department of Neurology, Massachusetts General Hospital, Boston, MA.
⁸ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA; and.
⁹ Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding