Integrative bioinformatic analysis delineates a mitochondrial-hematopoietic gene signature for diagnosis and immune characterization in myelodysplastic syndromes

Objective This study aimed to develop a mitochondrial and hematopoiesis-related differentially expressed genes (MH-related DEGs) signature for Myelodysplastic syndromes (MDS) diagnosis and to characterize its regulatory network and immune microenvironment.Methods MH-related DEGs were defined as the intersection of differentially expressed genes from three integrated microarray datasets (GSE145733, GSE19429, GSE81173) with a curated set of mitochondrial- and hematopoiesis-related genes from public databases. Functional enrichment, machine learning (logistic regression, support vector machine, LASSO), regulatory network (transcription factors, miRNA, RNA-binding proteins, and drug targets), immune infiltration characterization (ssGSEA), and RT-qPCR assessment were performed.Results Twenty-nine MH-related DEGs were identified, significantly enriched in MAPK and PI3K-Akt pathways. A 17-gene diagnostic signature showed high accuracy for MDS detection (AUC = 0.963). FGF2 was the highest-weighted predictor, with upregulation supported by RT-qPCR (p < 0.05), and potentially regulated by RUNX1 and miR-15/16/195/424/497 family. Valproic acid was predicted to be associated with multiple signature genes. Two MDS clusters with distinct immune infiltration patterns were identified, where CREB1 correlated with effector memory CD4 T cells in Cluster 1 (r = 0.461), while KITLG correlated with T follicular helper cells in Cluster 2 (r = 0.546), potentially co-regulated by the miR-27.Discussion This study proposes a mitochondrial-hematopoietic regulatory axis in MDS, with FGF2 as a candidate hub. The clusters and valproic acid prediction offer insights into advancing personalized diagnostics and combination therapy in MDS.Conclusion We developed a candidate signature requiring further validation and uncovered regulatory interactions linking mitochondrial dysfunction to immune dysregulation in MDS.