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| Pàgina inicial > Articles > Articles publicats > Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing |
(Instituto de Investigación en Biomedicina de Buenos Aires) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)| Data: | 2022 |
| Resum: | 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. |
| Ajuts: | European Commission PCI2021-122045-2B European Commission SLT/002/16/00374 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1080 Instituto de Salud Carlos III FPU17/02423 Instituto de Salud Carlos III CD19/00228 Agencia Estatal de Investigación RTI2018-094049-B-I00 |
| Nota: | This work was supported by MCIN/AEI/10.13039/501100011033 and European Union "NextGenerationEU"/PRTR" Project PCI2021-122045-2B. We thank CERCA Programme/Generalitat de Catalunya for institutional support. Work at M.E. laboratory is supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-project no. 2017SGR1080 of the Catalan Government (Generalitat de Catalunya); Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and European Regional Development Fund (ERDF) project no. RTI2018-094049-B-I00; the Cellex Foundation; and "la Caixa" Banking Foundation (LCF/PR/GN18/51140001). Studies at Roué lab were partially funded by the ERDF through the Interreg V-A Spain-France-Andorra (POCTEFA) program (EFA360/19, PROTEOblood project). J.C.S was recipient of a Sara Borrell research contract (CD19/00228) from Instituto de Salud Carlos III. L.B.P. laboratory receives support from IBioBA-MPSP-CONICET (FOCEM COF 03/11, PICT-PRH 2017-4668), MPI for Metabolism Research (Cologne, Germany) and MPI for Biophysical Chemistry (Gottingen, Germany). A.E.M. is a CONICET fellow. A.B.C is a fellow of the Spanish Ministry of Education and Vocational Training, under FPU contract no. FPU17/02423. M.E. is an ICREA Research Professor.We thank Josep Carreras Foundation for institutional support. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Publicat a: | Redox biology, Vol. 55 (september 2022) , p. 102408, ISSN 2213-2317 |
