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首页> 外文学位 >The role of BLIMP1 and A20 inactivation in the pathogenesis of diffuse large B-cell lymphoma.
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The role of BLIMP1 and A20 inactivation in the pathogenesis of diffuse large B-cell lymphoma.

机译：BLIMP1和A20失活在弥漫性大B细胞淋巴瘤发病机理中的作用。

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摘要

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal centre B-cell like (GCB) DLBCL and activated B-cell like (ABC) DLBCL. These phenotypic subtypes segregate with multiple genetic lesions, suggesting the involvement of different pathogenetic mechanisms. Biallelic inactivation of the BLIMP1 gene, the master regulator of plasma cell differentiation, has been found exclusively in the ABC subtype (∼24% of cases), however, the precise mechanism by which these lesions contribute to lymphoma development has yet to be fully elucidated. Similar to BLIMP1, the A20 gene, a negative regulator of NF-κB signaling, is inactivated by mutations and biallelic deletions in ABC-DLBCL (∼30% of cases), suggesting that A20 also plays a tumor suppressor role in this disease. The role of A20 inactivation and constitutive NF-κB activation in lymphomagenesis in vivo, however, has yet to be addressed. Here we investigated the role of BLIMP1 and A20 inactivation in the pathogenesis of DLBCL by using a multi-faceted approach, combining human genetic data, in vitro functional assays and in vivo mouse models.;To address the role of A20 inactivation in lymphomagenesis, we generated A20 conditional knockout mice and crossed them to the Cγ1-Cre deleter strain, to delete A20 specifically in GC B cells (A20Cγ1KO). A20 Cγ1HET and A20Cγ1KO mice generated increased plasma cells after immunization, suggesting that A20 regulates plasma cell differentiation and gene dosage is important in GC B-cells. Furthermore, A20 knockout splenic B cells had increased proliferative capacity and survival after mitogenic stimulation. Finally, we crossed the mice to the lymphoma-prone IμHA BCL6 mouse model to assess the potential cooperation between these two lesions in DLBCL pathogenesis. Addition of the IμHABCL6 transgene abrogated the increase in plasma cell formation and cooperated with A20 deletion to increase the GC B cell compartment. Long-term follow-up of these cohorts will provide critical information on the role of A20 as a tumor suppressor gene in vivo and on its cooperative activity with BCL6 deregulation in the pathogenesis of DLBCL.;With regards to BLIMP1 inactivation, we demonstrated that BLIMP1 is disrupted by truncating and missense mutations and biallelic deletions in one-third of ABC-DLBCL. We performed a variety of functional assays to validate that a subset of missense mutations impaired BLIMP1 function through protein instability or reduced transrepression activity. Additionally, translocations of BCL6, a master regulator of the germinal centre reaction, actively suppressed BLIMP1 expression in additional ∼22% of ABC-DLBCL. Finally, Blimp1 B-cell conditional knockout mice developed ABC-DLBCL, thus providing definitive in vivo proof that BLIMP1 is a tumor suppressor gene.
机译：弥漫性大B细胞淋巴瘤（DLBCL）是由至少两种不同的亚型组成的异质性疾病：生发中心B细胞样（GCB）DLBCL和活化B细胞样（ABC）DLBCL。这些表型亚型与多个遗传病变隔离，表明涉及不同的致病机制。仅在ABC亚型中发现了BLIMP1基因的双等位基因失活，它是浆细胞分化的主要调节剂（约占24％），但是，这些病变促成淋巴瘤发展的确切机制尚未完全阐明。 。与BLIMP1相似，A20基因是NF-κB信号的负调节剂，被ABC-DLBCL中的突变和双等位基因缺失所灭活（约30％的病例），表明A20在该疾病中也起着抑癌作用。然而，A20失活和组成型NF-κB激活在体内淋巴瘤发生中的作用尚待研究。在这里，我们通过多方面的方法，结合人类遗传数据，体外功能测定和体内小鼠模型，研究了BLIMP1和A20失活在DLBCL发病机理中的作用;为了解决A20失活在淋巴瘤发生中的作用，我们产生了A20条件性基因敲除小鼠，并将其与Cγ1-Cre缺失株杂交，以特异性缺失GC B细胞（A20Cγ1KO）中的A20。 A20Cγ1HET和A20Cγ1KO小鼠免疫后生成的浆细胞增加，表明A20调节浆细胞分化，基因剂量在GC B细胞中很重要。此外，有丝分裂刺激后，A20基因敲除的脾脏B细胞具有增强的增殖能力和存活率。最后，我们将小鼠转移至易发生淋巴瘤的IμHABCL6小鼠模型，以评估这两种病变在DLBCL发病机理中的潜在协同作用。 IμHABCL6转基因的添加消除了浆细胞形成的增加，并与A20缺失协同作用以增加GC B细胞区室。这些队列的长期随访将提供有关A20在体内作为抑癌基因的作用及其在BLBCL发病机理中与BCL6失调的协同活性的重要信息。关于BLIMP1的失活，我们证明了BLIMP1三分之一的ABC-DLBCL中的截短和错义突变以及双等位基因缺失会破坏TNF-α。我们进行了多种功能测定，以验证通过蛋白质不稳定或降低的反转录活性，错义突变的一个子集会损害BLIMP1功能。此外，生发中心反应的主要调节者BCL6的易位，在约22％的ABC-DLBCL中积极抑制了BLIMP1的表达。最后，Blimp1 B细胞条件性剔除小鼠发展了ABC-DLBCL，从而提供了体内明确的证据，证明BLIMP1是抑癌基因。

著录项

  • 作者

    Mandelbaum, Jonathan.;

  • 作者单位

    Columbia University.;

  • 授予单位 Columbia University.;
  • 学科 Biology Molecular.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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