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)的一种特殊亚型，存在信号转导和转录激活因子(STAT)6。我们最近的研究发现，PMBL来源的细胞系Medb-1和霍奇金来源的细胞系L1236和20例(36%)在STAT6 DNA结合域存在杂合性错义突变，而在25例DBLCL样本中未发现这种突变。突变的STAT6蛋白在HEK293细胞中的DNA结合能力降低，但在携带突变的STAT6基因的PMBL病例中，STAT6规范靶基因的表达没有下降。因此，我想解决的问题是，这些影响DNA识别元件区域的突变是否允许STAT6在非规范的STAT6气态位点上招募，从而驱动潜在癌基因的表达，从而可能参与淋巴肿瘤的发生。我们进一步观察到，PMBL和Hodgkin来源的细胞系都显示p-STAT6和BCL6存在于细胞核中，并且这两种因子在PMBL细胞系中的分布是相互排斥的。此外，我有第一个实验迹象表明，p-STAT6调节PMBL和Hodgkin细胞系中两个表达BCL6的mRNA(称为短转录)中的一个。因此，本工作将详细研究野生型(Wt)和突变型STAT6在pMBL和chl中bcl6短转录本转录调控中的作用。此外，对可能受突变的STAT6调控的新靶点基因的全面分析将有助于理解STAT6突变在癌症中的作用，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.