The ferroptosis landscape in acute myeloid leukemia

Abstract

Ferroptosis induction through the suppression of glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2) has proven to be an effective approach in eliminating chemotherapy-resistant cells of various types. However, a comprehensive understanding of the roles of GPX4 and AIFM2 in acute myeloid leukemia (AML) has not yet been achieved. Using cBioPortal, DepMap, GEPIA, Metascape, and ONCOMINE, we compared the transcriptional expression, survival data, gene mutation, methylation, and network analyses of GPX4- and AIFM2-associated signaling pathways in AML. The results revealed that high expression levels of GPX4 and AIFM2 are associated with an adverse prognosis for AML patients. Overexpression of AIFM2 correlated with elevated mutation frequencies in NPM1 and DNMT3A. GPX4 upregulation modulated the following pathways: GO:0045333, cellular respiration; R-HSA-5389840, mitochondrial translation elongation; GO:0009060, aerobic respiration; R-HSA-9609507, protein localization; and R-HSA-8953854, metabolism of RNA. On the other hand, the overexpression of AIFM2 influenced the following processes: GO:0048704, embryonic skeletal system morphogenesis; GO:0021546, rhombomere development; GO:0009954, proximal/distal pattern formation; and GO:0048732, gland development. This study identifies the high expression of GPX4 and AIFM2 as novel biomarkers predicting a poor prognosis for AML patients. Furthermore, ferroptosis induction may improve the stratified treatment of AML.

Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia

“…It has been consistently reported that expression of GPX4 is elevated in most of AML cells and cell lines compared to their normal myeloid counterparts [ 35 ]. In this line, high expression of GPX4 in AML cells may also favor cellular growth and increase transformation potential.…”

“…Recently Ma et al, using multiparametric analysis of GPX4 and Apoptosis Inducing Factor Mitochondria Associated 2 (AIFM2) also called ferroptosis suppressor protein (FSP1) expression and function identified high expression of both proteins as novel biomarkers of pejorative prognosis in AML [ 35 ]. AIFM2 is a NAD(P)H-dependent oxidoreductase that catalyzes reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic antioxidant that prevents ferroptosis.…”