A Ferroptosis Molecular Subtype-Related Signature for Predicting Prognosis and Response to Chemotherapy in Patients with Chronic Lymphocytic Leukemia

Abstract

Ferroptosis is a type of regulated cell death catalyzed by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder. However, the understanding of ferroptosis in CLL remains largely poor. In this study, we investigated the stratification and prognostic role of ferroptosis-related genes in CLL patients of ICGC cohort. We obtained fourteen genes with prognostic value by screening 110 ferroptosis-related genes (FRGs). Based on the expression profiles of these 14 genes, we classified CLL patients into two clusters. Most of the FRGs were highly expressed in cluster 1, and cluster 1 was associated with better overall survival (OS). Subsequently, we developed an eight-gene signature (TP63, STEAP3, NQO1, ELAVL1, PRKAA1, HELLS, FANCD2, and CDKN2A) by using LASSO analysis. This risk signature divided CLL patients into high- and low-risk groups. We used Cox regression analysis and ROC analysis demonstrated the risk signature was reliable and robust. And we validated the risk model in an external cohort (GSE22762). We also conducted enrichment analysis and genomic mutation analysis. Finally, we explored the potential effect of chemotherapy between the two risk groups. Our study contributed to understanding the role of ferroptosis in CLL and facilitated personalized and precision treatment.

High-throughput proteomics identifies THEMIS2 as independent biomarker of treatment-free survival in untreated CLL

“…As such, the high expression of ferritin may, speculatively, render M-CLL cells differentially susceptible to ferroptosis. Of note, a recent study correlated the expression of eight ferroptosis-related genes to the clinical outcome of CLL patients, and to the predicted in vitro susceptibility of CLL cells to udarabine, cyclophosphamide and ibrutinib, further indicating that ferroptosis may play an important role in the context of CLL (34).…”

Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia

“…On the basis of these patient datasets, including those in the Cancer Genome Atlas (TCGA), multiple groups have defined ferroptosis-related genes (FRGs) and have correlated their expression with patient survival to develop FRG scoring models that can predict prognosis and ex vivo drug sensitivities in association with their clinical characteristics in AML [ 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 ], acute lymphoblastic leukemia (ALL) [ 177 ], and CLL [ 178 , 179 ]. Interestingly, many FRG signatures are associated with immune-related pathways and immune cell infiltration predicted by CIBERSORTx gene-expression profiling analyses, which suggests that ferroptosis has relevance in anti-tumor immune responses and potentially in immunotherapy in leukemia.…”

Ferroptosis in Leukemia: Lessons and Challenges

“…For instance, Gong et 1). Meanwhile, they developed a risk signature containing eight ferroptosis-related genes for predicting the OS of CLL patients [60].…”

“…Several reports have shown the potential of triggering ferroptosis for chronic leukemia therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies [60][61][62][63]. For decades, cysteine metabolism has been identified to have a critical role in cancer cell proliferation and survival, and cysteine depletion has been indicated to inhibit cancer growth and induce tumor cell ferroptosis.…”