期刊
REDOX BIOLOGY
卷 55, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2022.102408
关键词
Glutathione; Ferroptosis; Acute lymphoblastic leukemia; GPX4; FSP1; DNA Methylation
资金
- MCIN/AEI
- European Union NextGenerationEU/PRTR Project [PCI2021-122045-2B]
- Catalan Government (Generalitat de Catalunya) [SLT/002/16/00374, 2017SGR1080]
- Ministerio de Ciencia e Innovacion (MCI)
- Agencia Estatal de Investigacion (AEI)
- European Regional Development Fund (ERDF) [RTI2018-094049-B-I00]
- Cellex Foundation
- la Caixa Banking Foundation [LCF/PR/GN18/51140001]
- ERDF through the Interreg V-A Spain-France-Andorra (POCTEFA) program [EFA360/19]
- Instituto de Salud Carlos III [CD19/00228]
- IBioBA-MPSP-CONICET [FOCEM COF 03/11, PICT-PRH 2017-4668]
- MPI for Metabolism Research (Cologne, Germany)
- MPI for Biophysical Chemistry (Gottingen, Germany)
- Spanish Ministry of Education and Vocational Training, under FPU [FPU17/02423]
Blood-derived cancer cells are selectively sensitive to compounds blocking the GSH-dependent anti-ferroptosis axis, which may have therapeutic significance for ALL.
Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the irondependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T- and B- acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.
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