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FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas

机译：FBXO11靶向BCL6降解，并在弥漫性大B细胞淋巴瘤中失活

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摘要

BCL6 is the product of a proto-oncogene implicated in the patho-genesis of human B-cell lymphomas1"2. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease3'4. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5,6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXOll-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXOii-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumor-igenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.
机译：BCL6是原癌基因的产物，涉及人B细胞淋巴瘤的发病机理[1]。2通过结合特定的DNA序列，BCL6控制涉及B细胞发育，分化和激活的多种基因的转录。 BCL6在成年期最常见的侵袭性弥漫性大B细胞淋巴瘤（DLBCL）的大多数患者中过表达，并且在B细胞中组成型表达BCL6的转基因小鼠会产生类似于人类疾病的DLBCLs3'4。 ，BCL6的过表达是通过其启动子的易位（〜40％）或超突变（〜15％）来实现的，但是，许多其他DLBCL却通过未知的机制过表达BCL6，在这里我们证明BCL6可以通过SKP1泛素化和蛋白酶体降解。 -CUL1-F-box蛋白（SCF）泛素连接酶复合物，其中包含孤立的F-box蛋白FBXO11（参考文献5,6），发现编码FBXO11的基因在多个DLBCL细胞系中被删除或突变。且FBXO11的失活与BCL6的水平增加和稳定性有关。同样，FBXO11在主要DLBCL中被删除或突变。值得注意的是，肿瘤衍生的FBXO11突变体显示出诱导BCL6降解的能力受损。 FBXOll缺失的DLBCL细胞中FBXO11表达的重建促进BCL6泛素化和降解，抑制细胞增殖并诱导细胞死亡。缺失FBXOii的DLBCL细胞在免疫缺陷小鼠中产生肿瘤，并且通过FBXO11重构抑制了肿瘤异基因性。我们揭示了控制BCL6稳定性的分子机制，并提出FBXO11中的突变和缺失通过BCL6稳定化有助于淋巴瘤发生。在DLBCLs中发现的缺失/突变主要是单等位基因，表明FBXO11是单倍型肿瘤抑制基因。

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  • 来源
    《Nature》 |2012年第7379期|p.90-93|共4页
  • 作者

    Shanshan Duan; Lukas Cermak; JuliaK. Pagan; Mario Rossi; Cinzia Martinengo; Paola Franciadi Celle; Bjoern Chapuy; Margaret Shipp; Roberto Chiarle; Michele Pagano;

  • 作者单位

    Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA,Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA;

    Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA,Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA;

    Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA,Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA;

    Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA;

    Department of Biomedical Sciences and Human Oncology, CERMS, University of Torino, 10126 Torino, Italy;

    San Giovanni Battista Hospital, Via Santena 7,10126 Torino, Italy;

    Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Department of Biomedical Sciences and Human Oncology, CERMS, University of Torino, 10126 Torino, Italy;

    Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA,Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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