2. Academic Validation
  3. Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing

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

  • Redox Biol. 2022 Jul 31;55:102408. doi: 10.1016/j.redox.2022.102408.
Lucas B Pontel 1,  Alberto Bueno-Costa 2,  Agustín E Morellato 3,  Juliana Carvalho Santos 4,  Gaël Roué 4,  Manel Esteller 5
Affiliations

Affiliations

  • 1 Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina. Electronic address: lpontel@carrerasresearch.org.
  • 2 Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
  • 3 Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
  • 4 Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
  • 5 Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain; Centro de Investigacion Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain. Electronic address: mesteller@carrerasresearch.org.
PMID: 35944469 DOI: 10.1016/j.redox.2022.102408
Abstract

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.

Keywords

Acute lymphoblastic leukemia; DNA Methylation; FSP1; Ferroptosis; GPX4; Glutathione.

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