European review for medical and pharmacological sciences · 2020
Atrophic endometrium in postmenopausal women referred to diagnostic hysteroscopy: a study to avoid unnecessary examinations.
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Giannella L, Delli Carpini G, Di Giuseppe J, Tsiroglou D, Papiccio M, Montanari M, Frega A, Ciavattini A
Аннотация
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 Coronin 1A (CORO1A) remain insufficiently defined.
METHODS: We integrated AML bone marrow single-cell RNA-seq (GSE154109) with bulk RNA-seq from TCGA (training) and GSE71014 (testing), and GTEx normal marrow. After batch correction, we profiled 3,524 PCD- related genes. Single-cell analyses (Seurat, Harmony) resolved hematopoietic and malignant populations; pathway activity was quantified by ssGSEA/GSVA. Survival modeling used a multi-algorithm framework (10 learners, 117 combinations). Immune features were inferred via IOBR; immunotherapy response via TIDE; drug sensitivity via OncoPredict. We analyzed DepMap AML cell lines (n = 29), correlating CORO1A CRISPR dependency (CERES) with CORO1A expression (log2 TPM) by Pearson's correlation in R. CORO1A function was tested by shRNA knockdown in HL-60 and THP-1 cells with CCK-8, Annexin V, and Western blot.
RESULTS: Malignant cells and monocytes/macrophages showed higher PCD enrichment than lymphoid clusters. Malignant cells upregulated MYC/E2F targets, DNA repair, fatty acid metabolism, with attenuated interferon signaling. From 3,524 genes, we derived a five-gene prognostic signature-CORO1A and PECAM1 (risk), and CLEC11A, ITGA4, AGTPBP1 (protective)-via optimal LASSO plus stepwise Cox (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 and sex. Risk score-associated transcripts were enriched for apoptosis, FoxO signaling, senescence, proteoglycans in cancer, and HTLV-1 pathways; 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; the 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 highly expressed in AML cell lines; knockdown reduced proliferation, decreased Bcl-2/Bax ratio by 1.5-fold, 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 that promoting AML cell survival.
METHODS: We integrated AML bone marrow single-cell RNA-seq (GSE154109) with bulk RNA-seq from TCGA (training) and GSE71014 (testing), and GTEx normal marrow. After batch correction, we profiled 3,524 PCD- related genes. Single-cell analyses (Seurat, Harmony) resolved hematopoietic and malignant populations; pathway activity was quantified by ssGSEA/GSVA. Survival modeling used a multi-algorithm framework (10 learners, 117 combinations). Immune features were inferred via IOBR; immunotherapy response via TIDE; drug sensitivity via OncoPredict. We analyzed DepMap AML cell lines (n = 29), correlating CORO1A CRISPR dependency (CERES) with CORO1A expression (log2 TPM) by Pearson's correlation in R. CORO1A function was tested by shRNA knockdown in HL-60 and THP-1 cells with CCK-8, Annexin V, and Western blot.
RESULTS: Malignant cells and monocytes/macrophages showed higher PCD enrichment than lymphoid clusters. Malignant cells upregulated MYC/E2F targets, DNA repair, fatty acid metabolism, with attenuated interferon signaling. From 3,524 genes, we derived a five-gene prognostic signature-CORO1A and PECAM1 (risk), and CLEC11A, ITGA4, AGTPBP1 (protective)-via optimal LASSO plus stepwise Cox (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 and sex. Risk score-associated transcripts were enriched for apoptosis, FoxO signaling, senescence, proteoglycans in cancer, and HTLV-1 pathways; 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; the 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 highly expressed in AML cell lines; knockdown reduced proliferation, decreased Bcl-2/Bax ratio by 1.5-fold, 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 that promoting AML cell survival.