Molecular Mechanisms of Diffuse Large B-Cell Lymphoma and the Complexities of Tumor Development

Diffuse large B-cell lymphoma (DLBCL), the most prevalent aggressive non-Hodgkin lymphoma, exhibits substantial molecular heterogeneity and arises from germinal center or post-germinal center B cells through recurrent genetic and epigenetic dysregulation of critical signaling pathways. Aberrations involving BCL6, MYC, MYD88, and components of B cell receptor and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling play central roles in lymphomagenesis, treatment resistance, and clinical outcomes. Gene expression profiling has defined major molecular subgroups in DLBCL, including germinal center B cell-like and activated B cell-like tumors, that show distinct pathogenesis and prognosis. High-risk entities, such as double- and triple-hit lymphomas, remain therapeutically challenging despite advances in immunochemotherapy. Recent progress in molecular diagnostics and targeted therapies, including immune checkpoint inhibition, Bruton tyrosine kinase inhibitors, B-cell lymphoma 2 (BCL2) antagonists, and Chimeric antigen receptor-T cells, has expanded precision-based treatment strategies. This review summarizes advances in understanding the molecular mechanisms of DLBCL and emphasizes emerging therapeutic approaches informed by genomic and microenvironmental discoveries.