Pathogenesis of diffuse large B cell lymphoma proteogenotypes
Menée à l'aide de lignées cellulaires, de modèles murins et d'une analyse protéomique, transcriptomique et génomique de 478 lymphomes diffus à grandes cellules, cette étude identifie 7 protéogénotypes reflétant des caractéristiques pathophysiologiques spécifiques dont un protéogénotype se caractérisant par un pronostic défavorable, une signature biologique spécifique ainsi qu'un microenvironnement immunitaire altéré, puis propose un cadre pour améliorer le diagnostic et la prise en charge thérapeutique
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 that span known molecular subtypes. PG4 is associated with poor outcome independent of established risk factors such as cell-of-origin, international prognostic index, or genetic features. PG4 contains activated B cell-like and germinal center B cell-like tumors and genetically unclassified cases. It shares a dark-zone-related B cell phenotype and shows enrichment for BTG1 mutations that can activate MYC. Single-cell sequencing and spatial transcriptomics reveal enhanced MYC and TCF3/4 transcriptional activity irrespective of MYC translocations. The PG4 tumor microenvironment is characterized by exhausted CD8+ T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.
Cancer Cell , article en libre accès, 2026