AUTHOR=Wang Wenjun , Liang Qian , Zhao Jingyu , Pan Hong , Gao Zhen , Fang Liwei , Zhou Yuan , Shi Jun 

TITLE=Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.970316

DOI=10.3389/fgene.2022.970316

ISSN=1664-8021

ABSTRACT=<p>Acute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue Expression (GTEx) project. The metabolism-related gene, <italic>SLC25A21</italic> was found to be significantly downregulated in AML, and was associated with high white blood cell (WBC) counts, high pretrial blood (PB) and bone marrow (BM) blast abundance, <italic>FLT3</italic> mutation, <italic>NPM1</italic> mutation, and death events (all <italic>p</italic> value &lt;0.05). We validated the expression of <italic>SLC25A21</italic> in our clinical cohort, and found that <italic>SLC25A21</italic> was downregulated in AML. Moreover, we identified low expression of <italic>SLC25A21</italic> as an independent prognostic factor by univariate Cox regression (hazard ratio [HR]: 0.550; 95% Confidence interval [CI]: 0.358–0.845; <italic>p</italic> value = 0.006) and multivariate Cox regression analysis (HR: 0.341; 95% CI: 0.209–0.557; <italic>p</italic> value &lt;0.05). A survival prediction nomogram was established with a C-index of 0.735, which indicated reliable prognostic prediction. Subsequently, based on the median <italic>SLC25A21</italic> expression level, patients in the TCGA-LAML cohort were divided into low- and high-expression groups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs highlighted growth factor binding, extracellular structure organization, cytokine‒cytokine receptor interaction, etc. The results of gene set enrichment analysis (GSEA) indicated that the epithelial-mesenchymal transition, KRAS signalling, oxidative phosphorylation, and reactive oxygen species pathways were enriched. Through gene coexpression and protein‒protein interaction (PPI) network analysis, we identified two hub genes, <italic>EGFR</italic> and <italic>COL1A2</italic>, which were linked to worse clinical outcomes. Furthermore, we found that lower <italic>SLC25A21</italic> expression was closely associated with a significant reduction in the levels of infiltrating immune cells, which might be associated with immune escape of AML cells. A similar trend was observed for the expression of checkpoint genes (<italic>CTLA4</italic>, <italic>LAG3</italic>, <italic>TIGIT</italic>, and <italic>HAVCR2</italic>). Finally, drug sensitivity testing suggested that the low-expression <italic>SLC25A21</italic> group is sensitive to doxorubicin, mitomycin C, linifanib but resistant to JQ1, belinostat, and dasatinib. Hence, our study demonstrated that a low expression level of <italic>SLC25A21</italic> predicts an unfavourable prognosis in patients with AML.</p>