Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their ...Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.展开更多
Objective The aim of the study was to systematically evaluate the correlation between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia.Methods Computer databases including PubMed,EMBASE,and Web of Scie...Objective The aim of the study was to systematically evaluate the correlation between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia.Methods Computer databases including PubMed,EMBASE,and Web of Science were searched for case-control studies on the association between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia.The retrieval period was from the establishment of the database to November 2020.Two researchers independently screened the literature,extracted the data,evaluated the risk of bias in the included studies,and used Stata 14.0 software for meta-analysis.Results A total of 48 case-control studies were included,with 10520 and 44049 cases in the case and control groups,respectively.The meta-analysis results showed that rs4132061 and rs11978267 of IKZF1 were significantly correlated with the risk of acute lymphoblastic leukemia(ALL).Conclusion Current evidence indicates that rs4132061 and rs11978267 of IKZF1 are significantly associated with the risk of B-cell ALL.展开更多
IKZF1(Ikaros family zinc finger 1,IKZF1)基因的编码蛋白Ikaros属于锌指DNA结合蛋白家族,是血液淋巴系统发育必需的转录因子,在造血系统的发育和分化过程中起着十分重要的作用,已经证明其是淋巴细胞和髓样细胞发育的主要调节子。IKZF...IKZF1(Ikaros family zinc finger 1,IKZF1)基因的编码蛋白Ikaros属于锌指DNA结合蛋白家族,是血液淋巴系统发育必需的转录因子,在造血系统的发育和分化过程中起着十分重要的作用,已经证明其是淋巴细胞和髓样细胞发育的主要调节子。IKZF1基因突变导致Ikaros功能的缺失会对淋巴细胞的发育产生不利的结果,甚至会促进白血病的发生[1]。展开更多
目的了解BCR/ABL阴性B系急性淋巴细胞白血病（B-ALL）患儿IKZF1基因拷贝数异常情况,并分析IKZF1基因拷贝数异常与该部分患儿预后的相关性。方法应用多重连接探针扩增（MLPA）技术检测180例初诊BCR/ABL阴性B-ALL患儿IKZF1基因拷贝数异常...目的了解BCR/ABL阴性B系急性淋巴细胞白血病（B-ALL）患儿IKZF1基因拷贝数异常情况,并分析IKZF1基因拷贝数异常与该部分患儿预后的相关性。方法应用多重连接探针扩增（MLPA）技术检测180例初诊BCR/ABL阴性B-ALL患儿IKZF1基因拷贝数异常情况。根据有无IKZF1基因缺失将其分成两组：IKZF1缺失组和IKZF1正常组。回顾性分析IKZF1拷贝数缺失与BCR/ABL阴性B-ALL患儿预后的关系。结果 180例患儿中共有27例（15.0%）患儿发生了IKZF1缺失,其中IKZF1基因8个外显子全部缺失者4例,单纯1号外显子缺失者17例,4～7号外显子缺失者3例,2～7号外显子缺失者3例。IKZF1缺失组患儿初诊时白细胞水平及流式MRD-高危组患儿的比例明显高于IKZF1正常组;IKZF1缺失组患儿多发生在无特殊融合基因异常的BCR/ABL阴性患儿,且IKZF1基因缺失患儿易伴随出现11、8、5、7、21号等染色体的异常。Kaplan-Meier法分析显示,IKZF1缺失组无病生存率（DFS）明显低于IKZF1正常组（0.740±0.096 vs 0.905±0.034,P=0.002）。Cox法分析显示在排除了年龄、性别、初始WBC、初诊时脑脊液状态、泼尼松松试验反应情况、染色体核型后,IKZF1缺失仍不利于患儿的DFS（P〈0.05）。结论部分BCR/ABL阴性B-ALL患儿存在IKZF1缺失,IKZF1缺失为BCR/ABL阴性B-ALL患儿DFS的独立危险因素。展开更多
基金supported by the National Natural Science Foundation of China(No.82404417)Key Project of North China University of Science and Technology(ZD-YG-202408)State Key Laboratory of National Security Specially Needed Medicines Program(No.LTMC2022ZZ006).
文摘Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.
基金Supported by the National Key Project of Neonatal Children (No. 1311200003303)Grants from the Science and Technology Bureau of Sichuan Province (No. 2021YJ0211 to Jinlin Wu)Grants from the Health Planning Committee of Sichuan Province (No. 20PJ070 to Jinlin Wu)
文摘Objective The aim of the study was to systematically evaluate the correlation between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia.Methods Computer databases including PubMed,EMBASE,and Web of Science were searched for case-control studies on the association between IKZF1 polymorphisms and the risk of acute lymphoblastic leukemia.The retrieval period was from the establishment of the database to November 2020.Two researchers independently screened the literature,extracted the data,evaluated the risk of bias in the included studies,and used Stata 14.0 software for meta-analysis.Results A total of 48 case-control studies were included,with 10520 and 44049 cases in the case and control groups,respectively.The meta-analysis results showed that rs4132061 and rs11978267 of IKZF1 were significantly correlated with the risk of acute lymphoblastic leukemia(ALL).Conclusion Current evidence indicates that rs4132061 and rs11978267 of IKZF1 are significantly associated with the risk of B-cell ALL.
文摘IKZF1(Ikaros family zinc finger 1,IKZF1)基因的编码蛋白Ikaros属于锌指DNA结合蛋白家族,是血液淋巴系统发育必需的转录因子,在造血系统的发育和分化过程中起着十分重要的作用,已经证明其是淋巴细胞和髓样细胞发育的主要调节子。IKZF1基因突变导致Ikaros功能的缺失会对淋巴细胞的发育产生不利的结果,甚至会促进白血病的发生[1]。
文摘目的了解BCR/ABL阴性B系急性淋巴细胞白血病（B-ALL）患儿IKZF1基因拷贝数异常情况,并分析IKZF1基因拷贝数异常与该部分患儿预后的相关性。方法应用多重连接探针扩增（MLPA）技术检测180例初诊BCR/ABL阴性B-ALL患儿IKZF1基因拷贝数异常情况。根据有无IKZF1基因缺失将其分成两组：IKZF1缺失组和IKZF1正常组。回顾性分析IKZF1拷贝数缺失与BCR/ABL阴性B-ALL患儿预后的关系。结果 180例患儿中共有27例（15.0%）患儿发生了IKZF1缺失,其中IKZF1基因8个外显子全部缺失者4例,单纯1号外显子缺失者17例,4～7号外显子缺失者3例,2～7号外显子缺失者3例。IKZF1缺失组患儿初诊时白细胞水平及流式MRD-高危组患儿的比例明显高于IKZF1正常组;IKZF1缺失组患儿多发生在无特殊融合基因异常的BCR/ABL阴性患儿,且IKZF1基因缺失患儿易伴随出现11、8、5、7、21号等染色体的异常。Kaplan-Meier法分析显示,IKZF1缺失组无病生存率（DFS）明显低于IKZF1正常组（0.740±0.096 vs 0.905±0.034,P=0.002）。Cox法分析显示在排除了年龄、性别、初始WBC、初诊时脑脊液状态、泼尼松松试验反应情况、染色体核型后,IKZF1缺失仍不利于患儿的DFS（P〈0.05）。结论部分BCR/ABL阴性B-ALL患儿存在IKZF1缺失,IKZF1缺失为BCR/ABL阴性B-ALL患儿DFS的独立危险因素。
