Unraveling novel therapeutic targets for diffuse large B-cell lymphoma: a plasma multi-omics study

Background Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma, exhibits genetic heterogeneity and variable treatment responses. Discovering new therapeutic targets is critical to improve outcomes. Given the lack of plasma protein studies for DLBCL, this study aims to first identify novel therapeutic targets based on plasma multi-omics and genome-wide association studies with further verifications. Methods By two-step training (N = 456,948 participants) and validation (N = 288,927 participants), druggable genes and proteins were identified through the mendelian randomization analyses of expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) using the largest DLBCL dataset of genome-wide association studies. Further verifications were conducted through colocalization analysis, risk factor and related disease analysis, single-cell analysis, ex-vivo experiments and transcriptomics. Results A total of 16 genes, 2 cis- and 3 trans-regulated plasma proteins were found to be potential targets for DLBCL with significant risks. The colocalization analysis revealed that six genes (APOM, C4A, C4B, CYP21A2, HCP5 and NEU1) and two proteins (MICB and IL17F) shared the causal genetic variants with DLBCL, suggesting their potential as therapeutic targets. The single-cell analysis for DLBCL tumors confirmed their cell type-specific expressions, suggesting that TUBB, with high risk for DLBCL, was highly expressed in malignant B cells with expression levels increasing as the tumor malignancy worsens. Further experiments and transcriptomics using the TUBB inhibitor demonstrated its anti-DLBCL efficacy, highlighting the therapeutic promise of targeting TUBB. Conclusion This study unravels a series of novel therapeutic targets that provide new insights into the development of DLBCL treatment.