Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Blood Cancer Discov. 2024 Sep 3;5(5):331-352. doi: 10.1158/2643-3230.BCD-23-0182.
Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL) are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin ligase with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiologic KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the bric-a-brac tramtrack broad domain of KLHL6 disrupted its localization and heterodimerization and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL. Significance: Oncogenic BCR signaling sustains DLBCL cells. We discovered that Cullin-3-RING E3 ubiquitin ligase substrate-adapter KLHL6 targets BCR heterodimer (CD79A/CD79B) for ubiquitin-mediated degradation. Recurrent somatic mutations in the KLHL6 gene cause corrupt BCR signaling by disrupting surface BCR homeostasis. Loss of KLHL6 expression and mutant-induced phenotypes associate with targetable disease characteristics in B-cell lymphoma. See related commentary by Leveille et al. See related commentary by Corcoran et al.
激活弥漫性大 B 细胞淋巴瘤（DLBCL）致癌 B 细胞受体（BCR）信号的病理机制在很大程度上尚不清楚。Kelch 样家族成员 6（KLHL6）编码一种 Cullin-3-RING E3 泛素连接酶的底物衔接子，其靶标尚未得到很好的确定，在 DLBCL 中经常发生突变。通过应用高通量蛋白质相互作用组筛选和功能表征，我们发现 KLHL6 通过靶向其信号亚基 CD79A 和 CD79B 来调节 BCR。生理 KLHL6 表达模式的缺失在 MCD/C5 样激活 B 细胞 DLBCL 中很常见，与较高的 CD79B 水平和不良预后相关。KLHL6 的 bric-a-brac tramtrack broad 结构域中的突变会破坏其定位和异二聚化，并增加表面 BCR 水平和信号转导，而 Kelch 结构域突变体则有相反的效果。KLHL6 突变体的功能障碍不仅限于近端 BCR 信号转导，其表型与 KLHL6 沉默不同。总的来说，我们的研究结果揭示了 KLHL6 中的反复突变如何改变 BCR 信号转导，并在 DLBCL 中诱导可治疗的表型特征。意义：致癌的 BCR 信号维持 DLBCL 细胞的生长。我们发现 Cullin-3-RING E3 泛素连接酶底物衔接子 KLHL6 将 BCR 异二聚体（CD79A/CD79B）靶向用于泛素介导的降解。KLHL6 基因的反复体细胞突变通过破坏表面 BCR 稳态引起腐败的 BCR 信号转导。KLHL6 表达缺失和突变诱导的表型与 B 细胞淋巴瘤中可靶向的疾病特征相关。请参阅 Leveille 等人的相关评论。请参阅 Corcoran 等人的相关评论。
