Objectives:B-cell lymphoma 6(BCL6)is a transcriptional repressor whose overexpression is closely linked to the progression of diffuse large B-cell lymphoma(DLBCL),making it a promising therapeutic target.This study ai...Objectives:B-cell lymphoma 6(BCL6)is a transcriptional repressor whose overexpression is closely linked to the progression of diffuse large B-cell lymphoma(DLBCL),making it a promising therapeutic target.This study aims to identify a novel small molecule,synthesized via proteolysis-targeting chimeras(PROTACs),capable of degrading BCL6,thereby inhibiting DLBCL growth and providing a foundation for future preclinical studies.Methods:The expression of BCL6 in DLBCL was analyzed using The Cancer Genome Atlas(TCGA)database and the Human Protein Atlas.Western blotting assays confirmed BCL6 expression in tumor cell lines,leading to the identification of the small molecule compound DZ-865B.To evaluate DZ-865B’s in vitro efficacy,multiple assays were performed,including protein immunoblotting,immunofluorescence,reverse transcription quantitative PCR,EDU proliferation,and soft agar cloning assays.Results:TCGA analysis revealed significant overexpression of BCL6 in DLBCL(p<0.05),corroborated by immunohistological staining and western blotting.DZ-865B induced BCL6 degradation in DLBCL cell lines(OCI-LY-1 and SU-DHL-4)in a concentration-and time-dependent manner,and induced the degradation of nuclear BCL6 through the ubiquitin-proteasome pathway.Notably,DZ-865B did not alter BCL6 mRNA levels but modulated downstream gene expression,leading to the activation of apoptosis pathway proteins and inhibition of DNA synthesis,effectively suppressing DLBCL cell growth.Conclusion:This study demonstrates that the small molecule DZ-865B targets and degrades BCL6 in DLBCL cells,promoting apoptosis and inhibiting cellular proliferation.These findings highlight DZ-865B as a potential therapeutic agent for diffuse large B-cell lymphoma.展开更多
目的:探讨弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者治疗前血清β2微球蛋白(β2-microglobnlin,β2-MG)和内皮细胞生长因子(vascular endothelial growth factor,VEGF)蛋白表达与Bcl-6和Ki-67表达的临床相关性。方法...目的:探讨弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者治疗前血清β2微球蛋白(β2-microglobnlin,β2-MG)和内皮细胞生长因子(vascular endothelial growth factor,VEGF)蛋白表达与Bcl-6和Ki-67表达的临床相关性。方法:2011-09-08-2013-02-16江苏省肿瘤医院初治49例DLBCL患者行CHOP方案化疗,Luminex液相芯片法检测治疗前血清VEGF和β2-MG蛋白表达水平,常规免疫组化法检测Bcl-6和Ki-67表达。结果:VEGF蛋白高表达合并Bcl-6高表达者多见于年龄>60岁的老年患者,阳性率为53.8%(7/13),P=0.048;合并Ki-67高表达者的各项临床特征间差异均无统计学意义,P>0.05。VEGF蛋白高表达合并Ki-67高表达者能获得更佳的疗效,P=0.008;完全缓解(CR)患者阳性率为4/7,部分缓解(PR)患者阳性率为50.0%(8/16)。β2-MG蛋白高表达合并Bcl-6和Ki-67高表达与各项临床特征间差异无统计学意义,P>0.05。结论:VEGF蛋白高表达合并Ki-67高表达与治疗疗效密切相关,两者同时高表达时DLBCL患者对CHOP治疗方案的敏感度高,治疗疗效好。β2-MG和VEGF蛋白表达结合临床常规免疫组化检测有望成为DLBCL临床诊断和治疗方案选择的新方法。展开更多
目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_...目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。展开更多
基金supported by the National Natural Science Foundation of China(82260716)the Key Research and Development Program of Ningxia(2023BEG02010).
文摘Objectives:B-cell lymphoma 6(BCL6)is a transcriptional repressor whose overexpression is closely linked to the progression of diffuse large B-cell lymphoma(DLBCL),making it a promising therapeutic target.This study aims to identify a novel small molecule,synthesized via proteolysis-targeting chimeras(PROTACs),capable of degrading BCL6,thereby inhibiting DLBCL growth and providing a foundation for future preclinical studies.Methods:The expression of BCL6 in DLBCL was analyzed using The Cancer Genome Atlas(TCGA)database and the Human Protein Atlas.Western blotting assays confirmed BCL6 expression in tumor cell lines,leading to the identification of the small molecule compound DZ-865B.To evaluate DZ-865B’s in vitro efficacy,multiple assays were performed,including protein immunoblotting,immunofluorescence,reverse transcription quantitative PCR,EDU proliferation,and soft agar cloning assays.Results:TCGA analysis revealed significant overexpression of BCL6 in DLBCL(p<0.05),corroborated by immunohistological staining and western blotting.DZ-865B induced BCL6 degradation in DLBCL cell lines(OCI-LY-1 and SU-DHL-4)in a concentration-and time-dependent manner,and induced the degradation of nuclear BCL6 through the ubiquitin-proteasome pathway.Notably,DZ-865B did not alter BCL6 mRNA levels but modulated downstream gene expression,leading to the activation of apoptosis pathway proteins and inhibition of DNA synthesis,effectively suppressing DLBCL cell growth.Conclusion:This study demonstrates that the small molecule DZ-865B targets and degrades BCL6 in DLBCL cells,promoting apoptosis and inhibiting cellular proliferation.These findings highlight DZ-865B as a potential therapeutic agent for diffuse large B-cell lymphoma.
文摘目的:探讨弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者治疗前血清β2微球蛋白(β2-microglobnlin,β2-MG)和内皮细胞生长因子(vascular endothelial growth factor,VEGF)蛋白表达与Bcl-6和Ki-67表达的临床相关性。方法:2011-09-08-2013-02-16江苏省肿瘤医院初治49例DLBCL患者行CHOP方案化疗,Luminex液相芯片法检测治疗前血清VEGF和β2-MG蛋白表达水平,常规免疫组化法检测Bcl-6和Ki-67表达。结果:VEGF蛋白高表达合并Bcl-6高表达者多见于年龄>60岁的老年患者,阳性率为53.8%(7/13),P=0.048;合并Ki-67高表达者的各项临床特征间差异均无统计学意义,P>0.05。VEGF蛋白高表达合并Ki-67高表达者能获得更佳的疗效,P=0.008;完全缓解(CR)患者阳性率为4/7,部分缓解(PR)患者阳性率为50.0%(8/16)。β2-MG蛋白高表达合并Bcl-6和Ki-67高表达与各项临床特征间差异无统计学意义,P>0.05。结论:VEGF蛋白高表达合并Ki-67高表达与治疗疗效密切相关,两者同时高表达时DLBCL患者对CHOP治疗方案的敏感度高,治疗疗效好。β2-MG和VEGF蛋白表达结合临床常规免疫组化检测有望成为DLBCL临床诊断和治疗方案选择的新方法。
文摘目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。
