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

原发性纵隔B细胞淋巴瘤（PMBL）是弥漫性大B细胞淋巴瘤（DBLCL）的一个独特亚型，存在组成性激活的信号转导和转录激活因子（STAT）6。我们最近的工作表明，MedB-1，PMBL衍生的细胞系，霍奇金淋巴瘤衍生的细胞系L1236和20 55例（36%）PMBL港口杂合错义突变的STAT 6 DNA结合域，而没有这样的突变被发现在25 DBLCL样品。突变的STAT 6蛋白在转染的HEK 293细胞中显示出降低的DNA结合能力，但在具有突变的STAT 6基因的PMBL病例中没有观察到STAT 6典型靶基因的表达降低。因此，我想解决的问题是，这些影响DNA识别元件相关区域的突变是否允许在非典型STAT 6 GAS位点上募集STAT 6，这些位点驱动潜在癌基因的表达，因此可能参与淋巴瘤的发生。我们进一步观察到，PMBL和Hodgkin衍生的细胞系都显示出p-STAT 6和BCL 6在细胞核中的存在，并且这两种因子的分布在PMBL细胞系中是相互排斥的。此外，我有第一个实验迹象表明，p-STAT 6调节PMBL和霍奇金细胞系中两种表达的BCL 6 mRNA（称为短转录本）之一。因此，这项工作将详细描述野生型（wt）和突变的STAT 6在PMBL和cHL的BCL 6短转录本的转录调控中的作用。此外，对突变的STAT 6调控的可能的新靶基因的一般分析将有助于理解STAT 6突变在癌症中的功能，并可能揭示新的潜在治疗靶点。

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.