Dual relevance of EIF2S1 in acute myeloid leukemia: linking poor prognosis to immune-metabolic states and leukemic cell fitness.

BACKGROUND: Most transcriptomic studies in acute myeloid leukemia (AML) have focused on transcriptional regulation, whereas the clinical and biological relevance of translation initiation factors remains insufficiently defined. Eukaryotic translation initiation factor 2 subunit alpha (EIF2S1) is a key regulator of translation initiation, but its prognostic significance and association with AML remain unclear. METHODS: Bulk RNA-seq data from the TCGA-LAML and GTEx cohorts were analyzed to evaluate EIF2S1 expression, prognostic value, associated biological programs, ssGSEA-derived immune-cell-associated signature scores, and quanTIseq-estimated immune-cell proportions. Single-cell RNA sequencing data were further examined to characterize the cellular distribution of EIF2S1 and subset-specific immune and metabolic transcriptional features. Finally, siRNA-mediated EIF2S1 knockdown assays were performed in THP-1 monocytic AML cells to assess its functional relevance. RESULTS: EIF2S1 was significantly upregulated in AML and independently associated with shorter overall survival in the TCGA-LAML cohort. High EIF2S1 expression was linked to translation initiation-related programs and immune- and myeloid-lineage-related transcriptional features, including stronger myeloid-lineage signals, weaker cytotoxic T-cell-related signatures, and increased expression of immune checkpoint and immunoregulatory genes, including LGALS9 and TGFB1. Single-cell analysis localized EIF2S1 enrichment primarily to monocyte-like subsets and associated it with mitochondrial metabolic and innate immune transcriptional programs. Functionally, EIF2S1 knockdown induced G0/G1 cell-cycle arrest, suppressed THP-1 cell proliferation, migration, and invasion, and promoted apoptosis. CONCLUSIONS: EIF2S1 is associated with adverse prognosis, translation initiation-related programs, and monocyte-like immune-metabolic transcriptional states in AML. Functional findings further suggest that EIF2S1 contributes to leukemic cell fitness. These results support EIF2S1 as a potential therapeutic target requiring further experimental and clinical validation.