A novel ferroptosis-related gene signature for predicting prognosis in multiple myeloma

Abstract

Background: Multiple myeloma (MM) is a highly malignant hematological tumor with a poor overall survival (OS). Due to the high heterogeneity of MM, it is necessary to explore novel markers for the prognosis prediction for MM patients. Ferroptosis is a form of regulated cell death, playing a critical role in tumorigenesis and cancer progression. However, the predictive role of ferroptosis-related genes (FRGs) in MM prognosis remains unknown.

Methods: This study collected 107 FRGs previously reported and utilized the least absolute shrinkage and selection operator (LASSO) cox regression model to construct a multi-genes risk signature model upon FRGs. The ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) were carried out to evaluate immune infiltration level. Drug sensitivity was assessed based on the Genomics of Drug Sensitivity in Cancer database (GDSC). Then the synergy effect was determined with Cell counting kit-8 (CCK-8) assay and SynergyFinder software.

Results: A 6-gene prognostic risk signature model was constructed, and MM patients were divided into high and low risk groups. Kaplan-Meier survival curves showed that patients in the high risk group had significantly reduced OS compared with patients in the low risk group. Besides, the risk score was an independent predictor for OS. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of the risk signature. Combination of risk score and ISS stage had better prediction performance. Enrichment analysis revealed immune response, MYC, mTOR, proteasome and oxidative phosphorylation were enriched in high risk MM patients. We found high risk MM patients had lower immune scores and immune infiltration levels. Moreover, further analysis found that MM patients in high risk group were sensitive to bortezomib and lenalidomide. At last, the results of the in vitro experiment showed that ferroptosis inducers (RSL3 and ML162) may synergistically enhance the cytotoxicity of bortezomib and lenalidomide against MM cell line RPMI-8226.

Conclusion: This study provides novel insights into roles of ferroptosis in MM prognosis prediction, immune levels and drug sensitivity, which complements and improves current grading systems.

Keywords: drug sensitivity; ferroptosis; multiple myeloma; risk signature; tumor immunity.