弥漫大B细胞淋巴瘤（DLBCL）是淋巴系统恶性肿瘤中最常见亚型，其高死亡率的主要因素为高度异质性和耐药性的产生。因此，进一步阐明DLBCL的发生发展机制一直是其基础和临床研究的关键。我们发现，磷酸戊糖途径异常可能与DLBCL异质性及CHOP方案耐药性存在联系，并可能受到胰岛因子1（Islet-1）的调控。在本课题中，我们将对临床标本进行检测，确定磷酸戊糖途径异常与DLBCL恶性程度、耐药性及预后的相关性。通过细胞和动物模型的建立，探讨DLBCL代谢异常的功能及Islet-1对其调控的具体分子机制：Islet-1可能通过Islet-1/Sirtuin2/G6PD复合体而去乙酰化激活关键酶G6PD，并促进Glut1表达和葡萄糖摄入，从而增强磷酸戊糖途径并降低CHOP药物敏感性。本课题是由肿瘤代谢异常的机理来探讨DLBCL异质性和耐药性的新视角，其顺利完成可为DLBCL有效靶向治疗提供新的线索。

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant tumor in lymphatic system. For the heterogeneity and chemoresistance, DLBCL causes high mortality. Therefore, the elucidation of molecular mechanisms responsible for DLBCL tumorigenesis and development is urgently required to improve current therapeutic approaches. In previous studies, we found that elevated pentose phosphate pathway (PPP) might be positively correlated to DLBCL heterogeneity and chemoresistance, and might be regulated by an aberrant overexpressed factor Islet-1 in DLBCL. In the present study, we will determine the correlation between PPP dysregulation and malignant degree, chemoresistance or prognosis in DLBCL by clinical specimens analysis. Through the establishment of cell and animal model, we attempt to provide evidences that Islet-1 might be able to activate Sirtuin2 expression and improve the key enzyme G6PD dimerization and activation by forming a Islet-1/Sirtuin2/G6PD deacetylating complex. Furthermore, Islet-1 has the potential to increase glucose uptake through promoting Glut1 gene transcription. Based on these two mechanisms, the Islet-1 stimulated PPP dysregulation might be able to counteract CHOP induced oxidative damage. Taken together, our study plans to uncover a previously unknown mechanism by which Islet-1 mediates abnormal PPP to reduce chemosensitive in DLBCL, and these results may shed lights on a novel promising approach for the treatment of DLBCL with Islet-1 overexpression and PPP dysregulation.