Bone marrow miRNA signatures differentiate Waldenström macroglobulinemia from multiple myeloma and reflect disease‑specific regulatory programs

Abstract Waldenström macroglobulinemia (WM) and multiple myeloma (MM) are biologically distinct monoclonal gammopathies with partly overlapping clinical and laboratory features. In this exploratory study, we compared WM with a non-IgM MM to investigate whether bone marrow miRNA expression patterns differ between these entities and whether selected miRNAs could provide biological or diagnostic insight. Small RNA sequencing of bone marrow-derived cell fractions identified eight miRNAs differentially expressed between WM and MM. Among them, miR-92a-3p and miR-155-5p were upregulated in WM and were subsequently validated by RT-qPCR, showing promising discriminatory performance in bone marrow samples. In contrast, analysis of circulating miRNAs in peripheral blood serum showed limited concordance with bone marrow expression and did not reliably distinguish WM from MM, suggesting that serum miRNA levels may be influenced by additional systemic, cellular, and microenvironmental factors. To explore the potential biological context of the dysregulated miRNAs, predicted target genes were integrated with protein–protein interaction network and functional enrichment analyses. These exploratory analyses highlighted several hub genes, including EGFR , KRAS , MAPK1 , STAT3 , PTEN , HIF1A , and CCND1, and suggested enrichment of pathways related to PI3K/Akt, MAPK, HIF-1, and EGFR signaling, cellular senescence, cell cycle, and immune regulation. Collectively, our findings indicate that selected bone marrow miRNAs, particularly miR-92a-3p and miR-155-5p, may help distinguish WM from MM in this cohort and may reflect differences in underlying cellular and regulatory programs. Further validation in independent cohorts, including diagnostically challenging IgM monoclonal gammopathies, is warranted.