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Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma

机译：弥漫性大B细胞淋巴瘤中的慢性活跃B细胞受体信号传导

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A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models3, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD 11 is required for constitutive NF-κB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD 11 isoforms that activate NF-κB, but the mechanism that engages wild-type CARD 11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-κ, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD 11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules6 of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
机译：通过研究人类淋巴瘤中的免疫球蛋白基因和工程小鼠模型已经推断出了B细胞受体（BCR）信号在淋巴瘤形成中的作用，但是还需要其致癌作用的遗传和功能证据。在这里，我们描述了一种“慢性活动” BCR信号传导形式，它是弥散性大B细胞淋巴瘤（DLBCL）的活化B细胞样（ABC）亚型中细胞存活所必需的。信号适配器CARD 11是ABC DLBCL中组成型NF-κB通路活性和生存所必需的。大约10％的ABC DLBCL具有激活NF-κB的突变CARD 11同工型，但在其他ABC DLBCL中参与野生型CARD 11的机制尚不清楚。 RNA干扰基因筛选显示，BCR信号成分，布鲁顿酪氨酸激酶，对于野生型CARD11的ABC DLBCL的存活至关重要。此外，敲除近端BCR亚基（IgM，Ig-κ，CD79A和CD79B）可杀死具有野生型CARD 11的ABC DLBCL，而不会杀死其他淋巴瘤。与抗原刺激的正常B细胞​​中的BCR相似，这些ABC DLBCL中的BCR在质膜中形成低扩散的突出簇。在ABC DLBCL活检样本中经常检测到影响CD79B和CD79A的基于免疫受体酪氨酸的活化基序（ITAM）信号模块6的体细胞突变，但在其他DLBCL中很少发现，而在Burkitt淋巴瘤或与黏膜相关的淋巴样组织淋巴瘤中则从未发现过。在18％的ABC DLBCL中，第一个ITAM酪氨酸CD79B的一个功能关键残基被突变。这些突变增加了表面BCR表达并减弱了Lyn激酶（BCR信号的反馈抑制剂）。这些发现将慢性活性BCR信号传导确立为ABC DLBCL的新发病机制，提示了几种治疗策略。

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  • 来源
    《Nature》 |2010年第7277期|88-92|共5页
  • 作者

    R. Eric Davis; Vu N. Ngo; Georg Lenz; Pavel Tolar; Ryan M. Young; et al;

  • 作者单位

    Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Laboratory of Immunogenetics, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA;

    Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, 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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