Integrated assessment of the clinical and biological value of ferroptosis-related genes in multiple myeloma

Abstract

Background Ferroptosis is an iron-dependent mode of cell death that could be induced by erastin and exert antitumor effects. However, the clinical and biological roles of ferroptosis-related gene (FRG) signature and the therapeutic value of erastin in multiple myeloma (MM) remained unknown. Methods Clinical and gene expression data of MM subjects were extracted from the Gene Expression Omnibus (GEO) public database. Univariable cox analysis was applied to determine FRGs related to survival and the least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a prognostic model. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and infiltrating immune status were also analyzed. We conducted in vitro experiments to investigate the combination therapy of erastin and doxorubicin. Results 17 FRGs were strongly associated with patient survival and 11 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low- and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. We also observed a close relevance between functional pathways and immune infiltration with risk scores. Moreover, we combined erastin and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS). Conclusions We demonstrated the important value of ferroptosis in patient prognosis and as a potential antitumor target for MM.

Ferroptosis in Haematological Malignancies and Associated Therapeutic Nanotechnologies

“…Furthermore, high expression of ferroptosis suppressor genes was correlated with reduced progression-free and overall survival in MM patients [57]. A number of groups have recently developed ferroptosisrelated gene signatures that can be used to predict MM patient prognosis [58], high-risk patients [59] and/or drug sensitivity [60]. Fu et al went on to show that erastin and doxorubicin synergistically reduced NCI-H929 and RPMI-8226 MM cell viability via GPX4 degradation and subsequent ROS generation [58].…”

“…A number of groups have recently developed ferroptosisrelated gene signatures that can be used to predict MM patient prognosis [58], high-risk patients [59] and/or drug sensitivity [60]. Fu et al went on to show that erastin and doxorubicin synergistically reduced NCI-H929 and RPMI-8226 MM cell viability via GPX4 degradation and subsequent ROS generation [58]. Similarly, ferroptosis induced by GPX4 inhibition (RSL3 or ML162) synergistically decreased proliferation when combined with bortezomib or lenalidomide in RPMI-8226 MM cells [60].…”

Construction and experimental validation of a novel ferroptosis‐related gene signature for myelodysplastic syndromes

“…Studies have demonstrated that FRGs have the potential to predict immune responses and clinical outcomes in hematological malignancies, including lymphoma, [23][24][25] leukemia, [26][27][28] and multiple myeloma. [29][30][31] In this study, we aimed to examine and validate the accuracy of FRGs as biomarkers for MDS. This study was initiated by performing differential expression analysis between MDS and control samples, followed by various machine learning methods to build a predictive model with differentially expressed FRGs.…”

“…Studies have demonstrated that FRGs have the potential to predict immune responses and clinical outcomes in hematological malignancies, including lymphoma, 23‐25 leukemia, 26‐28 and multiple myeloma 29‐31 . In this study, we aimed to examine and validate the accuracy of FRGs as biomarkers for MDS.…”

The dual role of ferroptosis in anthracycline-based chemotherapy includes reducing resistance and increasing toxicity

“… Tumour type Agent type Sample type Target Mechanism/effect Ref. Triple-negative breast cancer Doxorubicin In vitro (MDA-MB-231 cells) Isoliquiritin Upregulation of isoliquiritin to induce ferroptosis and attenuate chemoresistance [ 66 ] Triple-negative breast cancer Doxorubicin In vivo (mice) Phosphoglycerate dehydrogenase Downregulation of phosphoglycerate dehydrogenase to reduce glutathione and attenuate chemoresistance [ 67 ] Triple-negative breast cancer Doxorubicin In vitro (MDA-MB-231 cells) Glucose-6-phosphate dehydrogenase Downregulation of glucose-6-phosphate dehydrogenase to reduce glutathione and attenuate chemoresistance [ 68 ] Acute myeloid leukaemia Doxorubicin In vitro (HL-60 cells) p38α Upregulation of p38α to induce ferroptosis and attenuate chemoresistance [ 78 ] Acute myeloid leukaemia Daunorubicin In vivo (mice) Cystine Downregulation of cystine to induce ferroptosis and attenuate chemoresistance [ 79 ] Diffuse large B-cell lymphoma Doxorubicin In vitro (a panel of 16 cell lines) Ironomycin Upregulation of ironomycin to induce ferroptosis and attenuate chemoresistance [ 80 ] Multiple myeloma Doxorubicin In vitro (H929 and RPMI-8226 cells) Erastin Upregulation of erastin to induce ferroptosis and attenuate chemoresistance [ 81 ] Uterine sarcoma Doxorubicin In vitro (MES-SA and FU-MMT-1 cells) HSF1 Downregulation of HSF1 to induce ferroptosis and attenuate chemoresistance [ 85 ] Rhabdomyosarcoma Doxorubicin ...…”