Proteome-wide mendelian randomization identifies FCRL3 and LY9 as potential therapeutic targets for lymphoma.

BACKGROUND: Lymphoma is a common hematologic malignancy with limited treatment options. The research objective was to ascertain plasma proteins that could be targeted for lymphoma treatment. METHODS: We conducted proteome-wide mendelian randomization (PW-MR) analyses on blood proteins from the deCODE (N = 355,559) and Fenland (N = 10,708) studies. Protein-protein interaction (PPI), sensitivity analysis and external validation were used to identify potential drug targets. We analyzed enrichment analysis, single cell sequencing, drug prediction, molecular docking, mouse genome informatics (MGI), qRT-PCR and CCK-8 assays. RESULTS: PW-MR analyses predicted 37 proteins associated with lymphoma. Therein, 8 proteins, including APOBEC3G, TNFAIP6, LY75, MAPK3, SERPING1, CSF2RB, FCRL3, and LY9, interacted with known lymphoma drug targets. Through enrichment analysis, these 8 proteins were found to be linked to organism's response to stimuli and the proliferation of leukocytes. PheWAS identified LY75, SERPING1 and CSF2RB as associated with hematologic abnormalities and immune disorders. Single cell analysis revealed the expression enrichment of FCRL3 and LY9 in B cells. The affinity between 5 potential drug targets and predicted lymphoma drugs was identified by molecular docking, and the association of LY75, MAPK3, CSF2RB, LY9 with abnormalities in the hematopoietic system was confirmed in MGI. Finally, qRT-PCR showed that FCRL3 and LY9 mRNA levels were significantly down-regulated in diffuse large B-cell lymphoma (DLBCL) cells. In CCK-8 assay, predicted drugs amiodarone and chrysin inhibited DLBCL cell proliferation in dose-dependent and time-dependent manner. CONCLUSIONS: Our study identified 37 potential lymphoma drug targets, emphasizing FCRL3 and LY9 as valuable therapeutic candidates, and amiodarone and chrysin in clinical translational application.