The Strange Origin of Hodgkin Lymphoma Cells
Key Finding: Hodgkin lymphoma cells originate from B cells that abort their differentiation into plasma cells.
Researchers at Weill Cornell Medicine have uncovered a surprising origin for the hallmark cells of Hodgkin lymphoma. The study reveals that these cancerous cells (known as Reed-Sternberg cells) begin their lives as B cells—immune cells designed to produce antibodies—but then stop their normal development into plasma cells.
This detour leaves the cells in a unique, dysfunctional state. They downregulate typical B cell markers and upregulate plasma cell markers, yet fail to produce immunoglobulins (antibodies). The analysis, published on April 22 in Blood Cancer Journal, compared gene expression profiles from 18 primary tumors and four cell lines, contrasting Hodgkin lymphoma with primary mediastinal B cell lymphoma (PMBL) and multiple myeloma.
A Survival Mechanism: The Unfolded Protein Response
The study identified an unusually active pathway within these cells: the unfolded protein response (UPR).
This pathway may serve as a critical survival mechanism for the cancer cells.
The UPR is typically triggered when a cell is stressed by an accumulation of misfolded proteins. In Hodgkin lymphoma, this pathway appears to be hijacked, allowing the malignant cells to thrive. The findings suggest that targeting the UPR pathway could offer a new therapeutic strategy, potentially with fewer long-term side effects than standard chemotherapy.
Evading the Immune System
The research also explains how Hodgkin lymphoma cells avoid detection by the body's immune system. The cells downregulate SLAM-family ligands, such as CD48. This reduces their recognition by natural killer (NK) cells.
The tumor microenvironment itself shows a scarcity of NK cells, suggesting the lymphoma is actively repelling or excluding these immune sentinels.
New Diagnostic Potential
The findings open the door to more precise diagnostics. The protein PDIA6, which is linked to the UPR pathway, could serve as a new biomarker. This would help pathologists distinguish Hodgkin lymphoma from other lymphomas that may appear similar under a microscope.
Study Leadership and Funding
The study was co-led by Dr. Ethel Cesarman (Weill Cornell Medicine) and Dr. Lisa Giulino-Roth (NYU Langone Health). The first authors are Dr. Mikhail Roshal (Memorial Sloan Kettering) and Isabella Kong (Weill Cornell Medicine).
The research was supported by the National Institutes of Health, the Tri-I Training Program in Computational Biology and Medicine, the MSK Cancer Center Support Grant, and the Gant Family Foundation.