Issues

Hyperactive B-cell receptor (BCR) signaling is a hallmark of diffuse large cell lymphoma (DLBCL). Within BCR, antigen-binding immunoglobulin receptor is complexed with CD79, which mediates intracellular signaling and trafficking. Here Meriranta and colleagues reveal that KLHL6, recurrently mutated in DLBCL, regulates BCR surface levels by directly targeting CD79A and CD79B to ubiquitin-mediated degradation. By proteomic profiling and structurefunction characterization, mutations in BTB domain (mKHLH6^BTB) are shown to disrupt KHLH6 localization, heterodimerization and CD79 binding. DLBCL with mKHLH6^BTB or abnormal KHLH6 histology are enriched for MCD/C5-like features, poor outcome, and increased surface BCR levels and signaling, suggesting they may be sensitive to a potent CD79B-targeting therapeutic polatuzumab vedotin. Mutations in other domains have distinct phenotypic and functional consequences, suggesting roles beyond BCR. Across two large DLBCL cohorts, KLHL6 morphological features correlated with disease subtypes and clinical outcomes. Cumulatively, the findings could inform patient stratification for targeted therapy. For details, please see the article on p. 1577 and the accompanying commentary.