Data from <i>SPEN</i> Loss Drives Extrafollicular Diffuse Large B-cell Lymphoma with Female-Specific Lethality and Therapeutic Vulnerabilities

<jats:p>&lt;div&gt;Abstract &lt;p&gt;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 &lt;i&gt;SPEN&lt;/i&gt; and &lt;i&gt;NOTCH2&lt;/i&gt; 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.&lt;/p&gt; Significance:&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;</jats:p>