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.
Authors
- Lisa Giulino‐Roth (ORCID: https://orcid.org/0000-0002-6040-8644)
- Isabella Y. Kong (ORCID: https://orcid.org/0000-0002-7480-4525)
- Alexandra E. Kovach (ORCID: https://orcid.org/0000-0002-6742-6749)
- Joshua Brody (ORCID: https://orcid.org/0000-0002-0850-6730)
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- O Elemento
- Jonathan Reichel (ORCID: https://orcid.org/0000-0003-2613-7497)
- Megan S. Lim (ORCID: https://orcid.org/0000-0002-0415-2867)
- Ethel Cesarman (ORCID: https://orcid.org/0000-0003-3303-6299)
- Matthew James Oberley (ORCID: https://orcid.org/0000-0001-6419-2513)
- Sakellarios Zairis
- Mikhail Roshal (ORCID: https://orcid.org/0000-0002-9585-0790)
- Luigi Marchionni (ORCID: https://orcid.org/0000-0002-7336-8071)
- Sunita I. Park (ORCID: https://orcid.org/0000-0002-8606-0519)
- Bhavneet Binder
- Matthew J. Barth
- Amy Chadburn
- Nitya Gulati
- Wikum Dinalankara
- Raul Rabadan
- Matthew Teater
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Children's Hospital of Los Angeles (US)
- Cornell University (US)
- Caris Life Sciences (United States) (US)
- Fundación Josep Carreras Contra la Leucemia (ES)
- Children's Healthcare of Atlanta (US)
- Weill Cornell Medicine (US)
- Columbia University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2026-04-22
- DOI
- https://doi.org/10.1038/s41408-026-01502-1
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- Weill Cornell Medical College
- National Cancer Institute
- National Institute of General Medical Sciences