Pathogenesis of Diffuse Large B-cell Lymphoma Proteogenotypes

The clinical and molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features and spanning cell-of-origin (COO) as well as genetic subtypes. PG4 is associated with poor outcome, independent of known risk factors including COO, genetic features or the international prognostic index. PG4 is enriched for subsets of activated B-cell-like DLBCL, germinal-center-B-cell-like tumors and genetically unclassified cases. It shares a dark-zone related B-cell phenotype and an enrichment of BTG1 and TBL1XR1 mutations. Single-cell sequencing and spatial transcriptomics further reveals enhanced MYC and TCF3/4 transcriptional activity while MYC translocations were absent, as well as exhausted CD8 T cells as common driver mechanisms in PG4. Our proteogenomic framework identifies heretofore unknown biological heterogeneity among DLBCL tumors, including high-risk proteogenomic features that provide a basis for innovative diagnostic and therapeutic approaches.