Exploring the Molecular Mechanisms and Shared Genetic Characteristics of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma.

Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), but the mechanisms of progression remain unclear. Transcriptomic datasets procured from the Gene Expression Omnibus (GEO) underwent thorough analysis to ascertain disease-related modules using weighted gene co-expression network analysis. A prognostic model (MGUSscore) was constructed via least absolute shrinkage and selection operator (LASSO) regression within the GSE136337 cohort and validated across independent datasets (The Cancer Genome Atlas - multiple myeloma [TCGA-MM], GSE4581, GSE57317). Crucially, the investigation integrated original single-cell ATAC-seq profiling, immune landscape characterization, and pharmacogenomic sensitivity prediction. Protein-level disparities were validated in clinical specimens using immunohistochemistry and multiplex immunofluorescence. DAP3 and UBE2S were identified as central drivers of progression. The MGUSscore effectively stratified patients into risk categories, with high-risk individuals exhibiting significantly inferior survival outcomes (p < 0.001). Notably, the high-risk group was characterized by distinct immune infiltration patterns and predicted responsiveness to specific chemotherapies. Experimental validation confirmed markedly elevated DAP3 and UBE2S protein expression in MM compared to MGUS tissues. Collectively, DAP3 and UBE2S may constitute promising therapeutic targets for MM intervention, meriting additional investigative efforts.