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Integrated analysis of programmed cell death–related genes identifies CORO1A as an apoptosis-associated gene in acute myeloid leukemia

bioinformatics
cell-biology
oncology

Abstract

Background: Programmed cell death (PCD) governs tissue homeostasis and shapes tumor–immune interactions. In acute myeloid leukemia (AML), apoptosis evasion drives resistance and poor outcomes, yet the PCD landscape and the role of CORO1A remain underdefined.
Methods: We integrated AML bone marrow single-cell RNA-seq (GSE154109) with bulk RNA-seq from TCGA (training) and GSE71014 (testing), plus GTEx normal marrow. After batch correction/normalization, we profiled 3,524 iPCD-curated genes. Single-cell analyses (Seurat, Harmony) resolved hematopoietic and malignant populations; pathway activities were quantified by ssGSEA/GSVA using 50 MSigDB Hallmarks and PCD signatures. Differential expression used limma. Survival modeling employed a multi-algorithm framework (10 learners, 117 combinations), evaluated by C-index, ROC/AUC, and Kaplan–Meier. Immune features were inferred via IOBR (CIBERSORT, quanTIseq, MCP-counter, xCell, EPIC, ESTIMATE, TIMER). Immunotherapy response was estimated by TIDE; drug sensitivity by OncoPredict. CORO1A function was tested by shRNA knockdown in HL-60 and THP-1 cells with CCK-8, Annexin V–FITC/PI, and Western blot.
Results: Malignant cells and monocytes/macrophages showed higher PCD enrichment than lymphoid clusters. Malignant cells exhibited upregulated MYC/E2F targets, DNA repair, fatty acid metabolism, and reduced interferon signaling. From 3,524 genes, we derived a five-gene prognostic signature - CORO1A and PECAM1 (risk), CLEC11A, ITGA4, AGTPBP1 (protective)-via an optimal LASSO plus stepwise Cox model (mean C-index 0.72; TCGA 0.74; GSE71014 0.70). Discrimination was strong (AUCs: training 0.816/0.803/0.887 at 1/3/5 years; testing 0.711/0.765/0.749) and independent of age/sex. Risk score - associated transcripts were enriched for apoptosis, FoxO signaling, senescence, proteoglycans in cancer, and HTLV-1; GSEA indicated hematopoietic stemness and NRF2-upregulated programs. High-risk tumors had higher stromal/immune scores, lower purity, increased monocytes/macrophages/neutrophils, and reduced B/T/NK infiltration; risk score correlated with cytokines (CXCR3, IL10, PF4, PPBP). TIDE predicted greater immunotherapy benefit in high-risk patients. OncoPredict suggested higher sensitivity in the high-risk group to 5-fluorouracil, PI3K-AKT-mTOR inhibitors (afuresertib, pictilisib, taselisib, dactolisib), and the MET inhibitor savolitinib. CORO1A was overexpressed in AML lines; knockdown reduced proliferation and increased apoptosis.
Conclusions: Multi-omic integration of PCD-related genes delineates PCD-driven heterogeneity in AML and yields a robust five-gene prognostic model with therapeutic implications. CORO1A emerges as a potential apoptosis-associated oncogene promoting AML cell survival.
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