MYC与NDRG2相互调控在弥漫大B细胞淋巴瘤中的机制研究及NDRG2低表达的预后意义

Patients of diffuse large B-cell lymphoma (DLBCL) with MYC overexpression usually have a dismal outcome. However, effective treatment is still unavailable and the mechanism of MYC overexpression is less well understood. N-Myc downstream regulated gene 2 (NDRG2) is low expressed in most solid tumors and predicts a shorter survival. Our previous findings showed that NDRG2 had a low expression level in DLBCL patients samples which were negatively correlated to MYC expression. Besides, patients with NDRG2 low expression predict poor outcome compared with high expression cases. Prevous studies showed that the down regulation of NDRG2 was associated with methylation of the NDRG2 promoter region. The mechanism of NDRG2 expression in DLBCL is still unknown. We speculate that MYC can regulate NDRG2 expression and vice versa in the formation and progression of DLBCL. This project intends to investigate: the status of NDRG2 level and its prognosis in DLBCL patients; the epigenetic mechanism in the regulation of NDRG2 expression; the potenial mechanism of MYC and NDRG2 mutual regulation in DLBCL. By studying the molecular mechanism of MYC overexpression and the prognostic value of NDRG2 expression, we want to illustrate the therapeutic potential of targeting drugs with MYC overexpression DLBCL and provide novel ways of individualized treatment.

MYC基因过表达的弥漫大B细胞淋巴瘤（DLBCL）患者预后不良，目前尚无标准治疗方案，其异常表达机制尚无报道。N-myc下游调节基因（NDRG2）在多数肿瘤中存在低表达，提示预后不良。我们前期研究发现MYC过表达的DLBCL中存在NDRG2低表达，二者呈显著负相关，且NDRG2低表达的DLBCL患者预后不良。研究显示，NDRG2低表达可能与启动子区高甲基化有关，而DLBCL中其表达情况及机制不明。我们推测MYC与NDRG2在DLBCL发生发展中可能存在调控关系。本课题拟在前期研究的基础上，明确DLBCL患者中NDRG2表达的预后意义；探讨NDRG2低表达的表观遗传学调控机制；研究DLBCL中MYC与NDRG2相互调控关系在DLBCL发生发展中的潜在机制，为靶向MYC异常DLBCL治疗提供理论依据，为个体化治疗提供新途径。

弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, DLBCL）是最常见的非霍奇金淋巴瘤之一，占所有NHL的30%-40%。伴有MYC基因异常的DLBCL常预后不良，R-CHOP治疗反应率低，生存期短。MYC基因异常包括基因重排、基因扩增以及MYC基因mRNA和蛋白水平过表达，最终均可导致MYC蛋白过表达。我们前期研究证实MYC过表达与DLBCL患者不良预后有关。对于MYC过表达患者国内外尚无有效的标准一线治疗方案。我们发现在DLBCL患者中NDRG2蛋白与MYC蛋白表达存在负相关。通过从细胞及动物水平上对RNA及蛋白水平上分别研究，发现在DLBCL细胞中，MYC及Miz-1基因具有协同作用，两者形成完整的MYC/Miz-1复合体对NDRG2基因表达具有负向调控作用，相反，NDRG2过表达同样对MYC具有抑制作用。NDRG2蛋白低表达除了受到MYC/Miz-1复合体调控外，尚存在其他潜在机制，比如NDRG2基因启动子区CpG岛的甲基化，存在甲基化的情况往往表现为NDRG2蛋白的低表达，通过去甲基化药物处理，可以逆转NDRG2基因的低表达，在NDRG2基因低表达的患者中运用去甲基化药物治疗可能有望进一步改善这类患者的治疗效果。在DLBCL患者中存在NDRG2蛋白低表达，NDRG2低表达患者多数同时存在MYC蛋白过表达，NDRG2蛋白与MYC蛋白存在负相关，且MYC蛋白过表达或NDRG2蛋白低表达与DLBCL患者不良预后有关。