Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing

Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent 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 (...

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Bibliographic Details
Published in:Redox biology 2022-09, Vol.55, p.102408-102408, Article 102408
Main Authors: Pontel, Lucas B., Bueno-Costa, Alberto, Morellato, Agustín E., Carvalho Santos, Juliana, Roué, Gaël, Esteller, Manel
Format: Article
Language:English
Subjects:
Acute lymphoblastic leukemia
DNA Methylation
Ferroptosis
FSP1
Glutathione
GPX4
Research Paper
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Summary:Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent 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. [Display omitted] •Hematopoietic-derived cancer cell lines depend on GSH metabolism.•Acute lymphoblastic leukemia (ALL) cell lines are sensitive to ferroptosis inducers.•Ferroptosis suppressor protein 1 (FSP1) is silenced by DNA methylation in ALL.•Ferroptosis inducers might be a selective therapeutic option for ALL patients.
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2022.102408