Deregulation of stemness and senescence genes in bone marrow mesenchymal stem cells of multiple myeloma: implications for therapeutic approaches

PURPOSE: Multiple myeloma (MM) is a hematologic malignancy associated with a poor prognosis. MM-derived mesenchymal stromal cells (MM-MSCs) contribute to disease progression by creating a supportive stromal microenvironment for malignant cells. Elucidating transcriptomic alterations in MSCs may therefore facilitate the development of novel therapeutic strategies for treatment-resistant MM. METHODS: Total RNA was extracted from cultured MSCs isolated from bone marrow aspirates of patients with MM and normal donors (ND-MSCs). Expression of stemness markers (NANOG, OCT4) and senescence-associated genes (P16, P21, IL-6, IL-8) was analyzed using reverse transcription-quantitative polymerase chain reaction. Cellular senescence was assessed by senescence-associated β-galactosidase (SA-β-gal) staining. RESULTS: Compared with ND-MSCs, MM-MSCs demonstrated a higher percentage of SA-β-gal-positive cells. Gene expression analysis showed upregulation of P21 and IL-6 in MM-MSCs, whereas NANOG and OCT4 were significantly downregulated. Notably, this downregulation was consistent with analysis of a publicly available RNA sequencing dataset, supporting the validity of our findings. CONCLUSIONS: Consistent with previous reports of increased senescence, our findings demonstrate significant downregulation of stemness-related genes (NANOG, OCT4) in MSCs from newly diagnosed, untreated patients with MM. This concurrent dysregulation of stemness and increased senescent phenotype may contribute to the pathogenicity of the tumor microenvironment and represents a potential target for therapeutic intervention. CLINICAL TRIAL REGISTRATION: Not applicable. This study did not involve a clinical trial.