组蛋白去甲基化酶FBXL10在人弥漫性大B细胞淋巴瘤中的作用及机制研究

The diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoid cancer, there are still some patients that are resistant to first-line therapy or that undergo relapse, and the pathogenesis of DLBCL is not clear by now. In previous studies, we found that histone demethylase FBXL10 overexpressed in a variety of B cell lymphoma cell line, and the proliferation of DLBCL cell lines were inhibited or even blocked after FBXL10 knockdown, and it was found that FBXL10 was associated with the target gene expression of B-cell lymphoma 6 protein (BCL6). Recent evidences also show that histone demethylase FBXL10 plays an oncogene role in other tumors. Based on the previous study, we intend to clarify the function and role of FBXL10 in DLBCL firstly, it will be observed that the effect of FBXL10 on cell proliferation, cell cycle and apoptosis, and FBXL10 knockdown on tumor growth in vivo. Moreover, the molecular mechanism that FBXL10 promote DLBCL cell proliferation by regulating transcriptional activity of BCL6 target gene will be explored by the method of co-immunoprecipitation, co-localization in cell, dual luciferase reporter assay, and chromatin immunoprecipitation. Finally, these findings will be validated in clinical tumor tissue. It could provide a theoretical basis for lymphoma targeted therapy.

弥漫性大B细胞淋巴瘤（DLBCL）是成人淋巴瘤中最为常见的一种类型，其复发率高、对现有治疗具有抗性，目前关于DLBCL的发病机制仍不清楚。我们前期研究发现组蛋白去甲基化酶FBXL10在多种B细胞淋巴瘤株中高表达，降表达FBXL10使DLBCL细胞株的增殖受到明显抑制甚至阻滞，并发现FBXL10与B细胞淋巴瘤6蛋白(BCL6)靶基因表达相关。近年研究结果也表明FBXL10在其他肿瘤中的重要性。本研究拟从体外观察FBXL10对细胞增殖、周期及凋亡的影响，及体内研究FBXL10降表达对DLBCL发展的影响，明确FBXL10在DLBCL中的功能及作用；分子水平采用免疫共沉淀、细胞内共定位、双荧光素酶报告基因分析、染色质免疫共沉淀等方法，阐明FBXL10通过调控BCL6靶基因的转录活性促进DLBCL细胞增殖的作用机理，并在临床瘤组织中验证上述发现，为淋巴瘤的靶向治疗提供理论依据。

弥漫性大B细胞淋巴瘤（DLBCL）是成人淋巴瘤中最为常见的一种类型，其复发率高、对现有治疗具有抗性，目前关于DLBCL的发病机制仍不清楚。本研究拟从体外观察FBXL10对细胞增殖、周期及凋亡的影响，及体内研究FBXL10降表达对DLBCL发展的影响，明确FBXL10在DLBCL中的功能及作用；分子水平阐明FBXL10通过调控BCL6靶基因的转录活性促进DLBCL细胞增殖的作用机理，并在临床瘤组织中验证上述发现。我们研究发现组蛋白去甲基化酶FBXL10在多种B细胞淋巴瘤株中高表达，降表达FBXL10使DLBCL细胞株的增殖受到明显抑制甚至阻滞，在分子水平、细胞水平及组织水平从体内体外多层面多手段首次揭示了组蛋白去甲基化酶FBXL10在弥漫性大B淋巴细胞瘤的进展中发挥的重要作用，同时发现FBXL10通过募集BCOR-PRC1维持靶基因磷酸酶DUSP6的转录抑制，进而促进ERK1/2信号通路的激活。这些发现表明FBXL10可能成为DLBCL的一个有前途的治疗靶点，并建立表观遗传调控因子与激活性增殖信号通路的联系，为淋巴瘤的靶向治疗提供理论依据。.