TY - JOUR
T1 - Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers
AU - Yusuf, Rushdia Zareen
AU - Saez, Borja
AU - Sharda, Azeem
AU - van Gastel, Nick
AU - Yu, Vionnie W.C.
AU - Baryawno, Ninib
AU - Scadden, Elizabeth W.
AU - Acharya, Sanket
AU - Chattophadhyay, Shrikanta
AU - Huang, Cherrie
AU - Viswanathan, Vasanthi
AU - S'aulis, Dana
AU - Cobert, Julien
AU - Sykes, David B.
AU - Keibler, Mark A.
AU - Das, Sudeshna
AU - Hutchinson, John N.
AU - Churchill, Michael
AU - Mukherjee, Siddhartha
AU - Lee, Dongjun
AU - Mercier, Francois
AU - Doench, John
AU - Bullinger, Lars
AU - Logan, David J.
AU - Schreiber, Stuart
AU - Stephanopoulos, Gregory
AU - Rizzo, William B.
AU - Scadden, David T.
N1 - Funding Information:
This work was supported by grants from the following funders: Leukemia and Lymphoma Society (Research Fellow Career Development Award), Alex’s Lemonade Stand Foundation (Young Investigator Award), National
Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019001808
DO - 10.1182/blood.2019001808
M3 - Article
C2 - 32458004
AN - SCOPUS:85091469762
SN - 0006-4971
VL - 136
SP - 1303
EP - 1316
JO - Blood
JF - Blood
IS - 11
ER -