A large cohort of 66 primary lymphoma samples, including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), DH/TH lymphomas, and ISFN, was profiled by immunohistochemistry, RNA-scope, and flow cytometry to determine the IgH isotype expressed by malignant cells.
Nineteen representative cases were selected for single-cell RNA sequencing and B-cell receptor (BCR) clonotype analyses, enabling a high-resolution integration of transcriptional identity, clonal architecture, and immune composition.
Complementary bulk transcriptomics on 22 DH/TH lymphomas revealed that tumors with detectable IgH expression (IgH⁺) and those lacking it (IgH^UND) represent distinct biological entities. IgH⁺ lymphomas displayed immune activation signatures and T-cell–rich microenvironments, while IgH^UND cases showed proliferative, metabolically active, and immune-depleted profiles.
These findings, published in Blood Cancer Discovery (2025), demonstrated that IgH^UND lymphomas predominantly derive from isotype-switched B cells, establishing a molecular link between BCR class, tumor biology, and clinical aggressiveness.
In parallel, ISFN and early FL cases were subjected to single-cell and spatial transcriptomic profiling, revealing transcriptional and microenvironmental differences between reactive and pathological germinal centers colonized by BCL2-rearranged B cells. Pathological centers exhibited enrichment in cell survival and immune evasion programs, while reactive centers showed proliferative signatures and balanced immune cell infiltration.
These results provide the first spatially resolved molecular characterization of pre-neoplastic GC lesions, highlighting the earliest changes associated with FL initiation.
