XBP1-driven proliferative B cell subcluster in Diffuse Large B Cell Lymphoma linked to altered nucleotide metabolism

Current understanding of B cell heterogeneity in diffuse large B cell lymphoma (DLBCL) and its functional impact on disease progression remains incomplete. This study applies single-cell RNA sequencing to identify and characterize a distinct proliferation-related B cell subpopulation in DLBCL, aiming to address this knowledge gap.

We utilized dataset GSE182434 from the Gene Expression Omnibus (GEO) database for the analysis, with the aim of identifying genes that are specifically highly expressed in different cell clusters. The copy number variation analysis was performed using B cells of normal samples as the control. Thereafter, the cell-cell communication analysis was implemented to reveal the potential ligand-receptor pairs, and the functional enrichment analysis was performed to uncover the enriched pathways. Further, the potential transcription factors-target genes networks were plotted via SCENIC analysis, and a series of validation assays were implemented using DLBCL cells.

The single-cell landscape of DLBCL revealed a reduced proportion of B cells, CD8⁺ T cells, and naïve T cells. Malignant B cells exhibited chr1q amplification and chr6 deletion, with genes in these regions linked to immune suppression and impaired antigen presentation, respectively. Further subclustering identified a proliferative B cell subcluster (subcluster 2) enriched in nucleotide metabolism and cell cycle pathways. This subcluster was characterized by elevated XBP1 activity, regulating ER stress response, and downregulation of SPIB, RELB, and IRF factors involved in lymphocyte activation and interferon signaling. Functionally, XBP1 silencing suppressed DLBCL cells proliferation and invasion. Cell communication analysis revealed crosstalk between this B cell subpopulation and CD8+ T/NK cells via MIF-(CD74+CXCR4) and LTA-TNFRSF pathways.

This analysis has identified and characterized the proliferation-related B cells in DLBCL, which may provide some ideas for the treatment strategies in immune-oncology and cellular therapies.