A study using RNA sequencing to analyze Hodgkin and Reed–Sternberg (HRS) cells – the malignant cells in classic Hodgkin lymphoma (cHL) – has identified molecular features that may support diagnosis and improve understanding of disease biology.
HRS cells are difficult to study because they are rare within tumor tissue, often making up less than 1 percent of the sample. To address this, researchers used flow cytometry to isolate these cells from 18 patient samples before performing transcriptome sequencing and comparing them with surrounding B cells and related lymphomas.
The analysis showed clear differences in gene expression between HRS cells and normal B cells, including widespread loss of typical B-cell features. This supports the idea that HRS cells originate from B cells but undergo significant reprogramming.
One key finding was activation of the unfolded protein response (UPR), a cellular stress pathway usually seen in plasma cells. This pathway was not active in other related lymphomas. The study also identified strong expression of the protein PDIA6 in HRS cells, confirmed by immunohistochemistry, with minimal expression in surrounding tissue. This suggests PDIA6 could be explored as a diagnostic marker.
The study also found evidence of immune evasion. HRS cells showed reduced expression of molecules involved in natural killer (NK) cell recognition, including CD48. This was confirmed at the protein level, and fewer NK cells were present in tumor samples. These findings indicate that HRS cells may avoid immune detection by limiting NK cell activity.
When compared with primary mediastinal B-cell lymphoma, HRS cells showed overlapping pathways but distinct differences, including greater loss of B-cell identity and absence of certain diagnostic markers. This may help refine differential diagnosis between related lymphomas.
The researchers also assessed viral involvement using sequencing methods. Epstein–Barr virus was detected only in known positive cases, and no additional viral pathogens were identified.
Overall, the study highlights how targeted sequencing of tumor cells can identify diagnostic markers and clarify disease mechanisms. These findings may support the development of additional immunohistochemical or molecular tools to aid diagnosis and classification of cHL.
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