Abstract
Acute myeloid leukemia (AML) is a life-threatening hematologic malignant disease with high morbidity and mortality in both adults and children. Cuproptosis, a novel mode of cell death, plays an important role in tumor development, but the functional mechanisms of cuproptosis-related genes (CRGs) in AML are unclear. The differential expression of CRGs between tumors such as AML and normal tissues in UCSC XENA, TCGA and GTEx was verified using R (version: 3.6.3). Lasso regression, Cox regression and Nomogram were used to screen for prognostic biomarkers of AML and to construct corresponding prognostic models. Kaplan–Meier analysis, ROC analysis, clinical correlation analysis, immune infiltration analysis and enrichment analysis were used to further investigate the correlation and functional mechanisms of CRGs with AML. The ceRNA regulatory network was used to identify the mRNA-miRNA-lncRNA regulatory axis. Cuproptosis-related genes LIPT1, MTF1, GLS and CDKN2A were highly expressed in AML, while FDX1, LIAS, DLD, DLAT, PDHA1, SLC31A1 and ATP7B were lowly expressed in AML. Lasso regression, Cox regression, Nomogram and calibration curve finally identified MTF1 and LIPT1 as two novel prognostic biomarkers of AML and constructed the corresponding prognostic models. In addition, all 12 CRGs had predictive power for AML, with MTF1, LIAS, SLC31A1 and CDKN2A showing more reliable results. Further analysis showed that ATP7B was closely associated with mutation types such as FLT3, NPM1, RAS and IDH1 R140 in AML, while the expression of MTF1, LIAS and ATP7B in AML was closely associated with immune infiltration. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) revealed that biological functions such as metal ion transmembrane transporter activity, haptoglobin binding and oxygen carrier activity, pathways such as interferon alpha response, coagulation, UV response DN, apoptosis, hypoxia and heme metabolism all play a role in the development of AML. The ceRNA regulatory network revealed that 6 lncRNAs such as MALAT1, interfere with MTF1 expression through 6 miRNAs such as hsa-miR-32-5p, which in turn affect the development and progression of AML. In addition, APTO-253 has the potential to become an AML-targeted drug. The cuproptosis-related genes MTF1 and LIPT1 can be used as prognostic biomarkers in AML. A total of six lncRNAs, including MALAT1, are involved in the expression and regulation of MTF1 in AML through six miRNAs such as hsa-miR-32-5p.
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Data Availability
The data sets analyzed during the current study are available in the TCGA (https://portal.gdc.cancer.gov/) and GTEx (https://commonfund.nih.gov/gtex).
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Tianjin Key Medical Discipline (Specialty) Construction Project, TJYX2DXK-068C, Tianjin Medical University General Hospital Clinical Research Program, 22ZYYLCCG03
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YL: designed and conducted the whole research. XK: revised and finalized the manuscript. Both authors read and approved the final manuscript.
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10528_2023_10473_MOESM2_ESM.tiff
Supplementary file2 (TIFF 1260 KB) Functional enrichment analysis of CRGs. A–B GO analysis of CRGs. C–D KEGG analysis of CRGs. E GO and KEGG analysis of CRGs. CRGs cuproptosis-related genes; GO Gene Ontology; KEGG Kyoto Encyclopedia of Genes and Genomes
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Supplementary file3 (TIFF 427 KB) GSEA analysis of CRGs. A MTF1. B LIAS. C ATP7B. CRGs cuproptosis-related genes; GSEA Gene Set Enrichment Analysis
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Supplementary file4 (TIFF 1198 KB) Cox regression. B–C Prognostic values (OS) of MTF1 and LIPT1 expression in patients with AML evaluated by the Kaplan-Meier method (GSE2191). D–E ceRNA regulatory network. mRNAs were represented by the red diamonds, miRNAs by the blue ovals, lncRNAs by the green polygons, and targeted drug by a purple triangle
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Li, Y., Kan, X. Cuproptosis-Related Genes MTF1 and LIPT1 as Novel Prognostic Biomarker in Acute Myeloid Leukemia. Biochem Genet 62, 1136–1159 (2024). https://doi.org/10.1007/s10528-023-10473-y
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DOI: https://doi.org/10.1007/s10528-023-10473-y