Genetic and Transcriptomic Profiles Identify Potential Therapeutic Targets of Concurrent Follicular and Diffuse Large...

Concurrent follicular and diffuse large B-cell lymphoma (FL/DLBCL) and transformed follicular lymphoma (tFL) are distinct B-cell lymphoma entities, posing challenges for understanding pathogenesis and clinical management. The clinical characteristics of 98 FL/DLBCL, 31 tFL, 403 FL1-2/3A, and 608 DLBCL patients were analyzed. DNA sequencing was performed in these cohorts, and RNA sequencing was performed on 60 FL/DLBCL, 8 tFL, 175 FL1-2/3A, and 329 DLBCL patients. FL/DLBCL was characterized by localized disease, whereas tFL was associated with elevated LDH levels. Genomic analyses revealed that FL/DLBCL harbored frequent mutations in the Wnt signaling pathway but lacked the epigenetic alterations observed in FL, while tFL retained FL-associated epigenetic mutations and acquired additional alterations in cell cycle/p53 and JAK-STAT pathways. Both FL/DLBCL and tFL exhibited increased gene mutations related to the tumor microenvironment and B-cell differentiation, most notably CD70 and CD79B. Transcriptomic profiling further demonstrated enrichment of tumor microenvironment and B-cell differentiation-related pathways, consistent with the mutational landscape. Functionally, co-culture assays showed that knockdown of CD70 in B-lymphoma cells reduced naive CD4+ and CD8+ T-cell subsets, whereas CD79B^Y197H transfected B-lymphoma cells enhanced tumor cell viability. Our findings comprehensively characterize FL/DLBCL and tFL molecularly, elucidating their distinct pathogenesis and rationalize CD70 and CD79B targeted immunotherapies.