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

Abstract

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.