SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities.

Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune responses. By studying co-occurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extra-follicular trajectory. Using animal models and human specimens, we find 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 to 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.