The cohesin complex plays critical roles in genomic stability and gene expression through effects on 3D architecture. Cohesin core subunit genes are mutated across a wide cross-section of cancers, but not in germinal center (GC) derived lymphomas. In spite of this, haploinsufficiency of cohesin ATPase subunit Smc3 was shown to contribute to malignant transformation of GC B-cells in mice. Herein we explored potential mechanisms and clinical relevance of Smc3 deficiency in GC lymphomagenesis. Transcriptional profiling of Smc3 haploinsufficient murine lymphomas revealed downregulation of genes repressed by loss of epigenetic tumor suppressors Tet2 and Kmt2d. Profiling 3D chromosomal interactions in lymphomas revealed impaired enhancer-promoter interactions affecting genes like Tet2, which was aberrantly downregulated in Smc3 deficient lymphomas. Tet2 plays important roles in B-cell exit from the GC reaction, and single cell RNA-seq profiles and phenotypic trajectory analysis in Smc3 mutant mice revealed a specific defect in commitment to the final steps of plasma cell differentiation. Although Smc3 deficiency resulted in structural abnormalities in GC B-cells, there was no increase of somatic mutations or structural variants in Smc3 haploinsufficient lymphomas, suggesting that cohesin deficiency largely induces lymphomas through disruption of enhancer-promoter interactions of terminal differentiation and tumor suppressor genes. Strikingly, the presence of the Smc3 haploinsufficient GC B-cell transcriptional signature in human patients with GC-derived diffuse large B-cell lymphoma (DLBCL) was linked to inferior clinical outcome and low expression of cohesin core subunits. Reciprocally, reduced expression of cohesin subunits was an independent risk factor for worse survival int DLBCL patient cohorts. Collectively, the data suggest that Smc3 functions as a bona fide tumor suppressor for lymphomas through non-genetic mechanisms, and drives disease by disrupting the commitment of GC B-cells to the plasma cell fate.

凝聚素复合物通过影响 3D 结构在基因组稳定性和基因表达中发挥关键作用。Cohesin 核心亚基基因在广泛的癌症中发生突变，但在生发中心 (GC) 衍生的淋巴瘤中没有发生突变。尽管如此，黏连蛋白 ATP 酶亚基的单倍体不足SMC3显示有助于小鼠 GC B 细胞的恶性转化。在这里，我们探讨了潜在的机制和临床相关性SMC3GC淋巴瘤形成的缺陷。转录分析SMC3单倍体不足的鼠淋巴瘤揭示了表观遗传肿瘤抑制因子缺失抑制基因的下调春节2和公里2d. 分析淋巴瘤中的 3D 染色体相互作用揭示了影响基因的增强子-启动子相互作用受损，例如春节2, 在SMC3缺乏性淋巴瘤。春节2在 B 细胞从 GC 反应中退出、单细胞 RNA-seq 谱和表型轨迹分析中起重要作用SMC3突变小鼠揭示了对浆细胞分化最后步骤的承诺的特定缺陷。虽然SMC3缺乏导致GC B细胞结构异常，体细胞突变或结构变异没有增加SMC3单倍体不足的淋巴瘤，表明黏连蛋白缺乏通过破坏终末分化和肿瘤抑制基因的增强子-启动子相互作用而在很大程度上诱导淋巴瘤。引人注目的是，SMC3患有 GC 衍生的弥漫性大 B 细胞淋巴瘤 (DLBCL) 的人类患者中单倍体不足的 GC B 细胞转录特征与较差的临床结果和黏连蛋白核心亚基的低表达有关。相反，cohesin 亚基的表达降低是 DLBCL 患者组群中生存率降低的独立危险因素。总的来说，数据表明SMC3通过非遗传机制作为真正的淋巴瘤抑制因子发挥作用，并通过破坏 GC B 细胞对浆细胞命运的承诺来驱动疾病。