Integrative Network Analysis of Single-Cell RNA Findings and a Priori Knowledge Highlights Gene Regulators in Multiple Myeloma Progression

Multiple Myeloma (MM) is an incurable malignancy that progresses from asymptomatic precursor stages-Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM)-to active disease. Despite ongoing research, the molecular mechanisms driving this progression remain poorly understood. In this study, we aimed to uncover key regulatory factors involved in MM progression by integrating single-cell RNA sequencing (scRNA-seq) data with curated a priori biological knowledge of MM. To this end, we first integrated a priori knowledge from databases in a synthetic gene network map to play the role of an MM-related backbone to project findings from scRNA analysis on CD138⁺ Plasma Cells. This was followed by stage-specific regulatory network construction and analysis using Integrated Value of Influence (IVI) metrics to identify the most influential genes across disease stages. Our findings revealed <i>GSK3B</i>, <i>RELA</i>, <i>CDKN1A</i>, and <i>PCK2</i> as central regulators shared across multiple stages of the disease. Notably, several of these genes had not previously been included in established MM gene sets, highlighting them as prime candidates for biomarkers and drug targets.