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Abstract
A growing body of evidence suggests a key role of tumor microenvironment, especially for bone marrow mesenchymal stem cells (MSC), in the maintenance and progression of multiple myeloma (MM), through direct and indirect interactions with tumor plasma cells. Thus, this study aimed to investigate the gene expression and functional alterations of MSC from MM patients (MM-MSC) in comparison with their normal counterparts from normal donors (ND-MSC). Gene expression analysis (Affymetrix) was performed in MM-MSC and ND-MSC after in vitro expansion. To validate these findings, some genes were selected to be evaluated by quantitative real time PCR (RT-qPCR), and also functional in vitro analyses were performed. We demonstrated that MM-MSC have a distinct gene expression profile than ND-MSC, with 485 differentially expressed genes (DEG) - 280 upregulated and 205 downregulated. Bioinformatics analyses revealed that the main enriched functions among downregulated DEG were related to cell cycle progression, immune response activation and bone metabolism. Four genes were validated by qPCR - ZNF521 and SEMA3A, which are involved in bone metabolism, and HLA-DRA and CHIRL1, which are implicated in the activation of immune response. Taken together, our results suggest that MM-MSC have constitutive abnormalities that remain present even in the absence of tumors cells. The alterations found in cell cycle progression, immune system activation, and osteoblastogenesis suggest, respectively, that MM-MSC are permanently dependent of tumor cells, might contribute to immune evasion and play an essential role in bone lesions frequently found in MM patients.
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1 Discipline of Hematology and Hemotherapy, Federal University of São Paulo, UNIFESP, Department of Experimental and Clinical Oncology, São Paulo, Brazil (GRID:grid.411249.b) (ISNI:0000 0001 0514 7202)
2 University of Pennsylvania, Center for Sleep and Circadian Neurobiology, Pennsylvania, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
3 Faculty of Medicine of the University of São Paulo, FMUSP, Department of Pediatrics, São Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
4 Hematology, Fleury, Medicine and Health, São Paulo, Brazil (GRID:grid.11899.38)
5 University Nine of July, UNINOVE, Departament of Post-Graduation in Medicine, São Paulo, Brazil (GRID:grid.412295.9) (ISNI:0000 0004 0414 8221)
6 Federal University of ABC, UFABC, Center of Mathematics, Computation and Congnition, Santo André, Brazil (GRID:grid.412368.a) (ISNI:0000 0004 0643 8839)