Dissecting diffuse large B cell lymphoma heterogeneity: new insights from a state-specific molecular characterization

Mutational profiling revealed state-specific patterns: S1 harbored mutations in genes involved in epigenetic regulation, cytoskeletal organization, and tumor microenvironment (TME) interactions (CREBBP, EZH2, ACTB), whereas S5 was enriched for mutations promoting survival signaling, immune evasion, and differentiation blockade (MYD88, CD79B, TP53). Pathway analysis indicated that S1 was linked to cell adhesion, extracellular matrix remodeling, and inflammatory signaling, while S5 displayed enrichment of cell cycle deregulation, metabolic reprogramming, and immune evasion.

Accordingly, S1 tumors appear reliant on TME interactions, whereas S5 tumors adopt a predominantly TME-independent, intrinsically aggressive phenotype. Collectively, these findings delineate a biologically coherent framework linking pathway deregulation with cell state and ecotype specific mutational landscapes, refining DLBCL risk classification and adding an additional dimension to conventional prognostic models.