Abstract Background and Objectives Despite the discovery of cuproptosis as a new type of cell death, less is known about the role cuproptosis-related genes (CRGs) may play in B-cell Non-Hodgkin Lymphoma (NHL). There remained a lack of knowledge regarding the clinical and biological roles of CRG signatures and the therapeutic value of the potent copper ionophore (elesclomol) in B-cell NHL. In this study, the purpose is to investigate the prognostic value of CRGs and their relationship to the tumor immune microenvironment, as well as the mechanism of cuproptosis in B-cell NHL. Methods B-cell NHL patients’ clinical and gene expression data were retrieved from Gene Expression Omnibus (GEO). Our prognostic model was developed using least absolute shrinkage and selection operator (LASSO) regression analysis and univariate Cox analysis. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and immune features were also analyzed. Vitro experiments were conducted to investigate the combination therapy of elesclomol and doxorubicin, and to explore the application value in B-cell NHL. Results Seven CRGs were strongly associated with patient survival and 4 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. Correlations with clinical features showed that higher Risk-Score was significantly associated with advanced Ann Arbor stages, which were further confirmed in two validation cohorts. We also observed a close relationship between functional pathways and immune features with risk scores. Moreover, we combined elesclomol 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 CRG signatures in prognosis of B-cell NHL patients, and that may be a potential antitumor target for B-cell NHL.
Liu et al. (Wed,) studied this question.