Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
Por:
Pontel, LB, Bueno-Costa, A, Morellato, AE, Santos, JC, Roue, G and Esteller, M
Publicada:
1 sep 2022
Resumen:
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.
Filiaciones:
:
Josep Carreras Leukaemia Res Inst IJC, Canc Epigenet Grp, Barcelona, Catalonia, Spain
Max Planck Gesell, Inst Invest Biomed Buenos Aires IBioBA, CONICET Partner Inst, Buenos Aires, DF, Argentina
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Josep Carreras Leukaemia Res Inst IJC, Canc Epigenet Grp, Barcelona, Catalonia, Spain
Morellato, AE:
Max Planck Gesell, Inst Invest Biomed Buenos Aires IBioBA, CONICET Partner Inst, Buenos Aires, DF, Argentina
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Josep Carreras Leukaemia Res Inst IJC, Lymphoma Translat Grp, Barcelona, Catalonia, Spain
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Josep Carreras Leukaemia Res Inst IJC, Lymphoma Translat Grp, Barcelona, Catalonia, Spain
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Josep Carreras Leukaemia Res Inst IJC, Canc Epigenet Grp, Barcelona, Catalonia, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Catalonia, Spain
Univ Barcelona, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona, Catalonia, Spain
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