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Publication : SPEN Loss Drives Extrafollicular Diffuse Large B-cell Lymphoma with Female-Specific Lethality and Therapeutic Vulnerabilities.

First Author  Pelzer B Year  2026
Journal  Cancer Discov Volume  16
Issue  8 Pages  1666-1690
PubMed ID  42013317 Mgi Jnum  J:390490
Mgi Id  MGI:8398387 Doi  10.1158/2159-8290.CD-25-1458
Citation  Pelzer B, et al. (2026) SPEN Loss Drives Extrafollicular Diffuse Large B-cell Lymphoma with Female-Specific Lethality and Therapeutic Vulnerabilities. Cancer Discov 16(8):1666-1690
abstractText  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.
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