Data from SPEN Loss Drives Extrafollicular Diffuse Large B-cell Lymphoma with Female-Specific Lethality and Therapeutic Vulnerabilities
Year: 2026
Type: other
Abstract: Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCLs derive from follicular B cells engaged in adaptive immune responses. By studying cooccurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extrafollicular trajectory. Using animal models and human specimens, we find that this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory, and a distinct, autoimmune B cell–like state. This trajectory is associated with sex-biased outcomes: Female patients and mice exhibit reduced survival compared with males in our cohorts. Further analysis links this disparity to enhanced X-chromosome–linked expression and functionality of Toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy. Significance: The findings in this article support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.
Authors: Benedikt Pelzer, Cem Meydan, Isaac M. Spiegel, Ioannis Karagiannidis, Min Xia, Matt Teater, Emma M. Welter, Zowie E. Searcy, Laura K. Hilton, Darko Barisic, Amos Fong, Pengyan Fa, Shenon Sethi, Irem S. Isgor, Jessie J. Fielding, Alireza Karbalayghareh, Colin S. Burdette, Sravya Tumuluru, Sonia M. Debek, Sunjae Lee, Ramon Massoni-Badosa, Ceyda Durmaz, Eralda Salataj, Prasath Pararajalingam, Zhengming Chen, Richard J. Pelzl, Sanket Shah, Martin A. Rivas, Kenneth B. Hoehn, Coraline Mlynarczyk, Hannah M. Isles, Xiang Wang, Ahmet Dogan, Kojo S.J. Elenitoba-Johnson, David W. Scott, Kostiantyn Dreval, Ryan D. Morin, Christina S. Leslie, Rishi Puri, Jacob B. Geri, Christopher R. Chin, Amy Chadburn, Christopher E. Mason, Hans Christian Reinhardt, Montserrat C. Anguera, Wendy Béguelin, Leandro Venturutti, Ari M. Melnick
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7172315808
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