The role of wild type and mutant STAT6 in the regulation of the BCL6 promoter in primary mediastinal B cell and classical Hodgkin lymphoma

野生型和突变型STAT6在原代纵隔B细胞和经典霍奇金淋巴瘤中BCL6启动子调控中的作用

• 批准号: 60331643
• 负责人: Dr. Olga Ritz
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/60331643?language=en
• 关键词: role; wild; type; mutant; STAT6

Primary mediastinal B-cell Lymphoma (PMBL) is a distinct subtype of diffuse large Bcell lymphoma (DBLCL) exibiting constitutively activated Signal Transducer and Activator of Transcription (STAT) 6. Our recent work revealed that MedB-1, a PMBLderived cell line, and Hodgkin-derived cell line L1236 and 20 of 55 (36%) PMBL cases harbour heterozygous missense mutations in the STAT6 DNA binding domain, whereas no such mutation was found in 25 DBLCL samples. The mutant STAT6 proteins showed a decreased DNA binding ability in transfected HEK293 cells, but no decrease in expression of STAT6 canonical target genes was observed in PMBL cases with a mutated STAT6 gene. Therefore I would like to address the question if these mutations, which affect the region involved in DNA recognition element, permits the recruitment of STAT6 on non-canonical STAT6 GAS sites, that drive the expression of potential oncogenes and, therefore, might participate in lymphomagenesis. We further observed that both, PMBL and Hodgkin derived cell lines, show the presence of the p-STAT6 and BCL6 in the nuclei and that the distribution of these two factors is mutually exclusive in PMBL cell lines. Additionally, I have first experimental indications that p-STAT6 regulates one of two expressed BCL6 mRNA (called short transcript) in PMBL and Hodgkin cell lines. Consequently, this work will characterize in detail the role of wild type (wt) and mutated STAT6 in the transcriptional regulation of BCL6 short transcript in PMBL and cHL. Moreover, the general analysis of possible new target genes regulated by mutated STAT6 will help to understand the function of STAT6 mutations in cancer and might reveal new, potentially therapeutic targets.

原发性纵隔 B 细胞淋巴瘤 (PMBL) 是弥漫性大 B 细胞淋巴瘤 (DBLCL) 的一种独特亚型，表现出组成型激活的信号转导子和转录激活子 (STAT) 6。我们最近的研究表明，MedB-1（PMBL 衍生细胞系）和霍奇金衍生细胞系 L1236 以及 55 例 (36%) PMBL 病例中的 20 例存在杂合错义 STAT6 DNA 结合域发生突变，而 25 个 DBLCL 样本中未发现此类突变。突变的 STAT6 蛋白在转染的 HEK293 细胞中显示出 DNA 结合能力降低，但在具有突变 STAT6 基因的 PMBL 病例中未观察到 STAT6 典型靶基因表达的降低。因此，我想解决以下问题：这些影响 DNA 识别元件相关区域的突变是否允许在非经典 STAT6 GAS 位点上招募 STAT6，从而驱动潜在癌基因的表达，因此可能参与淋巴瘤发生。我们进一步观察到 PMBL 和霍奇金衍生细胞系均显示细胞核中存在 p-STAT6 和 BCL6，并且这两个因子的分布在 PMBL 细胞系中是相互排斥的。此外，我的第一个实验表明 p-STAT6 调节 PMBL 和霍奇金细胞系中两种表达的 BCL6 mRNA（称为短转录本）之一。因此，这项工作将详细描述野生型 (wt) 和突变型 STAT6 在 PMBL 和 cHL 中 BCL6 短转录物的转录调控中的作用。此外，对突变 STAT6 调控的可能新靶基因的一般分析将有助于了解 STAT6 突变在癌症中的功能，并可能揭示新的潜在治疗靶点。