Pink1调控DLBCL细胞CD20表达和利妥昔耐药机制的研究

在临床实践中，肿瘤的标准化治疗为提高肿瘤的治愈率和延长肿瘤病人的生存期起到了极其重要作用，然而其疗效仍然存在显著的个体差异，这种差异在以化疗和靶向治疗为主要手段的肿瘤中表现得尤为突出。耐药细胞的产生是导致弥漫大B细胞淋巴瘤（DLBCL）治疗失败的重要原因之一，CD20缺失或减少直接影响利妥昔单抗联合化疗治疗复发/难治DLBCL的疗效。近年的研究证明，组蛋白去乙酰化可使CD20基因静默，抑制CD20蛋白表达。而利妥昔单抗也可以引起弥漫大B细胞淋巴瘤表面CD20减少，造成继发性耐药。我们的研究发现，CD20水平与利妥昔单抗疗效密切相关。丝氨酸/苏氨酸激酶Pink1可激活组蛋白去乙酰化酶HDAC抑制CD20基因MS4A1表达。敲除Pink1不仅增加CD20基因和蛋白表达，而且提高DLBCL对利妥昔单抗的敏感性。本项目将研究 Pink1/HDACs/CD20相互关系和作用机制，探索Pink1在利妥

In clinical practice, the standardized treatment of tumors has played an extremely important role in improving the cure rate and prolonging the survival of tumor patients. However, there are still significant individual differences in its efficacy, and this difference is particularly prominent in tumors with chemotherapy and targeted therapy. The generation of drug-resistant cells is an important reason for the failure of treatment of diffuse large B-cell lymphoma (DLBCL). Loss of CD20 is a major obstacle for the retreatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL) with Rituximab-associated regimens. Recent studies demonstrated that Histone deacetylation causes gene silencing and inhibits CD20 expression. Treatment with Rituximab significantly reduced CD20 surface expression at the protein levels. We found that the levels of CD20 protein surface expression were significantly and positively correlated with the sensitivities of cells to Rituximab. Serine / threonine kinase Pink1 activates histone deacetylase HDAC and inhibits CD20 gene MS4A1 expression. Knockdown Pink1 not only increases CD20 gene and protein expression, but also increases DLBCL sensitivity to Rituximab. This project will study the mechanism and relationship between Pink1 / HDACs / CD20, explore the role of Pink1in Rituximab resistance, seeking a new treatment for relapsed / refractory diffuse large B-cell lymphoma.