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

In this study, we explore the interplay between SPEN and NOTCH2 truncating mutations, identifying an alternative, extra-follicular, trajectory of diffuse large B cell lymphomas (DLBCL) transformation. Our findings challenge the traditional germinal centre-centric model of lymphomagenesis, showing that marginal zone B cells (MZB) can give rise to aggressive lymphomas with autoimmune/aged B cells (AiBC)-like features, under the influence of these compound mutations. At a mechanistic level, we found that SPEN loss re-routes NOTCH2-driven transcriptional programs, promoting a ZEB2-driven cell fate that blocks plasmacytic differentiation and skews B cell identity toward a MZB/AiBC mixed phenotype. We further show that SPENTRUNC/NOTCH2TRUNC-mutant lymphomas are associated with reduced overall survival of female DLBCL patients, due to X-chromosomal transcriptional perturbations. By characterizing their unique molecular dependencies, we identify actionable features in this aggressive DLBCL subset, paving the way for new precision medicine strategies that address the disease’s heterogeneity.