Cohesin Core Complex Gene Dosage Contributes to Germinal Center Derived Lymphoma Phenotypes and Outcomes.
Cohesin Core Complex Gene Dosage Contributes to Germinal Center Derived Lymphoma Phenotypes and Outcomes.
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DOI：
10.3389/fimmu.2021.688493
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发表时间：
2021
影响因子：
7.3
通讯作者：
Melnick AM
中科院分区：
文献类型：
--
作者：
Rivas MA;Durmaz C;Kloetgen A;Chin CR;Chen Z;Bhinder B;Koren A;Viny AD;Scharer CD;Boss JM;Elemento O;Mason CE;Melnick AM
粘着蛋白复合物通过影响3D结构在基因组稳定性和基因表达中起关键作用。粘着蛋白核心亚基基因在癌症的广泛横截面中突变，但在生发中心（GC）衍生的淋巴瘤中不突变。尽管如此，在小鼠中，粘附素ATP酶亚基Smc 3的单倍不足被证明有助于GC B细胞的恶性转化。在此，我们探讨了Smc 3缺陷在GC淋巴瘤发生中的潜在机制和临床意义。Smc 3单倍不足小鼠淋巴瘤的转录谱显示，表观遗传肿瘤抑制因子Tet 2和Kmt 2d的丢失抑制了基因的下调。分析淋巴瘤中的3D染色体相互作用显示，增强子-启动子相互作用受损，影响Tet 2等基因，Tet 2在Smc 3缺陷型淋巴瘤中异常下调。Tet 2在B细胞退出GC反应中起着重要作用，Smc 3突变小鼠的单细胞RNA-seq图谱和表型轨迹分析揭示了浆细胞分化最终步骤的特定缺陷。虽然Smc 3缺陷导致GC B细胞的结构异常，但Smc 3单倍不足淋巴瘤中的体细胞突变或结构变体没有增加，这表明粘附素缺陷主要通过破坏终末分化和肿瘤抑制基因的增强子-启动子相互作用诱导淋巴瘤。引人注目的是，在患有GC衍生的弥漫性大B细胞淋巴瘤（DLBCL）的人类患者中Smc 3单倍不足GC B细胞转录特征的存在与较差的临床结果和低表达的粘附素核心亚基有关。相反，粘附素亚单位表达减少是DLBCL患者队列中生存率较差的独立风险因素。总的来说，这些数据表明Smc 3通过非遗传机制作为淋巴瘤的真正肿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。
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.
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DOI：
10.1016/j.bbcan.2016.05.002
发表时间：
2016-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Hill VK;Kim JS;Waldman T
通讯作者：
Waldman T
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
5.8
作者：
Koren, Amnon;Massey, Dashiell J.;Robinson, Peter
通讯作者：
Robinson, Peter
影响因子：
4.4
作者：
Lazaris C;Kelly S;Ntziachristos P;Aifantis I;Tsirigos A
通讯作者：
Tsirigos A