PRDM1基因在结外NK/T细胞淋巴瘤-鼻型中表达丢失机制及临床病理意义研究

PRDM1(Positive regulatory domain containing 1 with zinc finger domain) is a key transcription factor in the maturation and differentiation of lymphocytes and has received much attention as a tumour suppressor gene in the mechanisms of lymphomagenesis.Our previous investigations showed that PRDM1 inactivation is common in extranodal NK/T cell lymphoma, nasal type (EN-NK/T-NT), an important lymphoma with high incidence in China,and is associated with the clinical and biological characteristics of EN-NK/T-NT.The mechanisms of PRDM1 inactivation involved in genetic and epigenetic regulation including gene deletion, promoter methylation, and miRNA regulation.The interactive or combined mechanisms may implicate in the pathogenesis of EN-NK/T-NT.Thus, we are planning to further investigate the mechanisms of PRDM1 inactivation, to identify the direct target gene of PRDM1,to reveal its specific gene expression profile,and to clarify the biological significance in EN-NK/T-NT.Our results can be expected to provide further insights into the molecular basis of its high infiltration feature and to offer new evidence for the clinical treatment of EN-NK/T-NT.

PRDM1（positive regulatory domain containing 1 with zinc finger domain）为淋巴细胞成熟分化中重要的转录因子，也是近年来淋巴瘤发病机制研究中受到高度关注的肿瘤抑制基因。本组前期研究表明：PRDM1基因在我国高发的重要淋巴瘤类型-鼻腔结外NK/T细胞淋巴瘤中存在普遍表达丢失，并与肿瘤的临床生物学特性相关。其失活的机制涉及基因缺失、启动子甲基化、microRNA调节等遗传学及表遗传学方面，这些机制相互或联合作用可能参与该肿瘤发生。本研究拟在此基础上进一步阐明PRDM1在该肿瘤表达丢失的机制，证明其表达对该肿瘤细胞生物学特性的调节作用，并确定在该肿瘤细胞中其直接调节的靶基因，以及相关的特异基因表达谱，并分析这些分子改变的临床生物学意义，以深入揭示该肿瘤高度侵袭性生物学特性的分子基础，并为临床治疗提供新的思路及证据。

本研究小组应用基因重组、基因表达谱、荧光原位杂交等分子技术，研究发现PRDM1蛋白在EN-NK/T-NT肿瘤中普遍表达丢失，并具有预后评估价值，可能作为肿瘤抑制性转录因子参与EN-NK/T-NT肿瘤发生发展。PRDM1蛋白表达丢失与6q21、PRDM1基因丢失、miR-223异常高表达、DNA甲基化作用有关，而且DNA甲基化、miR-223水平、基因丢失对PRDM1蛋白表达丢失的具有协同调节作用。EN-NK/T-NT肿瘤中JAK/STAT3、PI3K/AKT信号通路异常活化，组蛋白甲基化相关基因EZH2和H3K27me异常高表达，并且和抑癌基因PRDM1表达有关。这些信号相关的基因具有重要的临床病理学意义及预后评估价值，抑制JAK/STAT3、PI3K/AKT通路有望成为PRDM1阳性EN-NK/T-NT的治疗手段。