Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Sternberg cells reveals escape from NK cell recognition and an unfolded protein response

Classic Hodgkin lymphoma (cHL) shares mutations with primary mediastinal B cell lymphoma (PMBL) but differs in histology, clinical behavior, and phenotype. To define transcriptional programs underlying these differences, we performed flow cytometric cell sorting and low-input RNA sequencing of Hodgkin and Reed-Sternberg (HRS) cells from eighteen primary tumors, paired intra-tumoral B cells, and four cHL cell lines, and compared them with RNA-sequencing data from 40 PMBL cases. Transcriptomic profiling revealed that HRS cells undergo abortive plasma cell differentiation with robust activation of the unfolded protein response (UPR), a feature shared with multiple myeloma but absent in diffuse large B cell lymphoma and PMBL. HRS cells also demonstrated profound immune evasion, including suppression of B cell identity genes and loss of natural killer cell recognition through downregulation of SLAM family ligands such as CD48. Comparative analysis with PMBL highlighted shared oncogenic programs and key distinctions: HRS cells exhibited greater loss of B cell identity, absence of GCB- and plasma cell markers, and unique upregulation of cytoskeletal and mitotic pathways consistent with their multinucleated morphology. These findings establish HRS cells as aberrantly differentiated GCB cells with partial plasmacytic features, UPR activation and distinct immune evasion strategies.