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

Autores
Pontel, Lucas Blas; Bueno Costa, Alberto; Morellato, Agustín Ezequiel; Carvalho Santos, Juliana; Roué, Gaël; Esteller, Manel
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Bueno Costa, Alberto. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Morellato, Agustín Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Carvalho Santos, Juliana. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Roué, Gaël. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Esteller, Manel. Universidad de Barcelona; España. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); . Centro de Investigación Biomédica en Red de Cáncer; España. Institució Catalana de Recerca i Estudis Avancats; España
Materia
ACUTE LYMPHOBLASTIC LEUKEMIA
DNA METHYLATION
FERROPTOSIS
FSP1
GLUTATHIONE
GPX4
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/210449
Acceder
id CONICETDig_ac5270c8ba5efff2e2f8d916fab94d1a
oai_identifier_str oai:ri.conicet.gov.ar:11336/210449
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencingPontel, Lucas BlasBueno Costa, AlbertoMorellato, Agustín EzequielCarvalho Santos, JulianaRoué, GaëlEsteller, ManelACUTE LYMPHOBLASTIC LEUKEMIADNA METHYLATIONFERROPTOSISFSP1GLUTATHIONEGPX4https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ferroptosis 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.Fil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);Fil: Bueno Costa, Alberto. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);Fil: Morellato, Agustín Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Carvalho Santos, Juliana. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);Fil: Roué, Gaël. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);Fil: Esteller, Manel. Universidad de Barcelona; España. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); . Centro de Investigación Biomédica en Red de Cáncer; España. Institució Catalana de Recerca i Estudis Avancats; EspañaElsevier2022-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/210449Pontel, Lucas Blas; Bueno Costa, Alberto; Morellato, Agustín Ezequiel; Carvalho Santos, Juliana; Roué, Gaël; et al.; Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing; Elsevier; Redox Biology; 55; 9-2022; 1-112213-2317CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S221323172200180Xinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2022.102408info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:04:01Zoai:ri.conicet.gov.ar:11336/210449instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:04:01.848CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
title Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
spellingShingle Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
Pontel, Lucas Blas
ACUTE LYMPHOBLASTIC LEUKEMIA
DNA METHYLATION
FERROPTOSIS
FSP1
GLUTATHIONE
GPX4
title_short Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
title_full Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
title_fullStr Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
title_full_unstemmed Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
title_sort Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing
dc.creator.none.fl_str_mv Pontel, Lucas Blas
Bueno Costa, Alberto
Morellato, Agustín Ezequiel
Carvalho Santos, Juliana
Roué, Gaël
Esteller, Manel
author Pontel, Lucas Blas
author_facet Pontel, Lucas Blas
Bueno Costa, Alberto
Morellato, Agustín Ezequiel
Carvalho Santos, Juliana
Roué, Gaël
Esteller, Manel
author_role author
author2 Bueno Costa, Alberto
Morellato, Agustín Ezequiel
Carvalho Santos, Juliana
Roué, Gaël
Esteller, Manel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ACUTE LYMPHOBLASTIC LEUKEMIA
DNA METHYLATION
FERROPTOSIS
FSP1
GLUTATHIONE
GPX4
topic ACUTE LYMPHOBLASTIC LEUKEMIA
DNA METHYLATION
FERROPTOSIS
FSP1
GLUTATHIONE
GPX4
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Bueno Costa, Alberto. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Morellato, Agustín Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Carvalho Santos, Juliana. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Roué, Gaël. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi);
Fil: Esteller, Manel. Universidad de Barcelona; España. Institut D`investigació Biomedica de Girona Dr. Josep Trueta (idib`gi); . Centro de Investigación Biomédica en Red de Cáncer; España. Institució Catalana de Recerca i Estudis Avancats; España
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/210449
Pontel, Lucas Blas; Bueno Costa, Alberto; Morellato, Agustín Ezequiel; Carvalho Santos, Juliana; Roué, Gaël; et al.; Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing; Elsevier; Redox Biology; 55; 9-2022; 1-11
2213-2317
CONICET Digital
CONICET
url http://hdl.handle.net/11336/210449
identifier_str_mv Pontel, Lucas Blas; Bueno Costa, Alberto; Morellato, Agustín Ezequiel; Carvalho Santos, Juliana; Roué, Gaël; et al.; Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing; Elsevier; Redox Biology; 55; 9-2022; 1-11
2213-2317
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S221323172200180X
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2022.102408
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269832848867328
score 13.13397

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