Characterization of cuproptosis identified immune microenvironment and prognosis in acute myeloid leukemia.

Background: Recent studies have reported that cuproptosis, a novel cell death pathway, strongly correlates with mitochondrial metabolism. In addition, the studies reported that cuproptosis plays a role in the development of several cancers and is regulated by protein lipoylation. During cuproptosis, copper binds to the lipoylated proteins and mediates cancer progression. However, the role of cuproptosis in acute myeloid leukemia (AML) patients is yet to be explored.

Methods: This study curated seven cuproptosis-related-genes (CRGs): FDX1, DLAT, PDHB, PDHA1, DLD, LIAS, and LIPT1 to determine cuproptosis modification patterns and the CRGs signature in AML. The CIBERSORT and ssGSEA algorithms were utilized to evaluate the infiltration levels of different immune cell subtypes. A cuproptosis score system based on differentially expressed genes (DEGs) was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The developed cuproptosis score system was validated using two immunotherapy datasets, IMvigor210 and GSE78220.

Results: Three distinct cuproptosis regulation patterns were identified using the Beat AML cohort. The results demonstrated that the three cuproptosis regulation patterns were correlated with various biological pathways and clinical outcomes. Tumor microenvironment (TME) characterization revealed that the identified cuproptosis regulation patterns were consistent with three immune profiles: immune-desert, immune-inflamed, and immune-excluded. The AML patients were grouped into low- and high-score groups based on the cuproptosis score system abstracted from 486 cuproptosis-related DEGs. Patients with lower cuproptosis scores were characterized by longer survival time and attenuated immune infiltration. It was found that lower cuproptosis scores were strongly correlated with lower somatic mutation frequency. Moreover, patients with lower cuproptosis scores presented more favorable immune responses and dual clinical benefits among external validation cohorts.

Conclusions: Cuproptosis phenotypes are significantly correlated with immune microenvironment complexity and variety. Cuprotopsis regulates the response of cancer cells to the immune system. Quantitatively assessing cuproptosis phenotypes in AML improves the understanding and knowledge regarding immune microenvironment characteristics and promotes the development of therapeutic interventions.