DNA crosslinking and recombination-activating genes 1/2(RAG1/2)are required for oncogenic splicing in acute lymphoblastic leukemia

查看全文 作　　者：Hao [1]Zhang;Nuo [1]Cheng;Zhihui [1]Li;Ling [1,7]Bai;Chengli [2,3]Fang;Yuwen [1]Li;Weina [1]Zhang;Xue [1]Dong;Minghao [1]Jiang;Yang [4]Liang;Sujiang [1]Zhang;Jianqing [1]Mi;Jiang [1]Zhu;Yu [2,3]Zhang;Sai-Juan [1]Chen;Yajie [5,6]Zhao;Xiang-Qin [1]Weng;Weiguo [1,5,6]Hu;Zhu [1]Chen;Jinyan [1,8,9]Huang;Guoyu [1]Meng

机构地区：[1]Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine,Rui-Jin Hospital,School of Medicine and School of Life Sciences and Biotechnology,Shanghai JiaoTong University,Shanghai 200025,P.R.China;[2]Key Laboratory of Synthetic Biology,CAS Center for Excellence in Molecular Plant Sciences,Chinese Academy of Sciences,Shanghai 200032,P.R.China;[3]University of Chinese Academy of Sciences,Beijing 100049,P.R.China;[4]Department of Hematologic Oncology,State key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong 510060,P.R.China;[5]Department of Geriatrics,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,P.R.China;[6]Medical Center on Aging of Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,P.R.China;[7]Department of Laboratory Medicine,West China Hospital,Sichuan University,Chengdu,Sichuan 610044,P.R.China;[8]Biomedical Big Data Center,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310000,P.R.China;[9]Cancer Center,Zhejiang University,Hangzhou,Zhejiang 310000,P.R.China

出　　处：《Cancer Communications》索引2021年第41卷第11期,共21页

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:81970132,81770142,81800144,31800642;Shanghai Science and Technology Committee,Grant/Award Number:20JC1410600;Shanghai Guangci Translational Medical Research Development Foundation;Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support,Grant/Award Number:20152504;The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institute of Higher Learning;Samuel Waxman Cancer Research Foundation。 摘　　要：Background:Abnormal alternative splicing is frequently associated with carcinogenesis.In B-cell acute lymphoblastic leukemia(B-ALL),double homeobox 4 fused with immunoglobulin heavy chain(DUX4/IGH)can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript(ERGalt)and other splicing variants.However,the molecular mechanism underpinning this process remains elusive.Here,we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia.Methods:The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients.X-ray crystallography,small angle X-ray scattering(SAXS),and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element(DRE)-DRE sites.The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity.To check whether recombination-activating gene 1/2(RAG1/2)was required for DUX4/IGH-driven splicing,the proximity ligation assay,co-immunoprecipitation,mammalian two hybrid characterizations,in vitro RAG1/2 cleavage,and shRNA knock-down assays were performed.Results:We reported previously unrecognized intron retention events in Ctype lectin domain family 12,member A abnormal transcript(CLEC12Aalt)and chromosome 6 open reading frame 89 abnormal transcript(C6orf89alt),where also harbored repetitive DRE-DRE sites.Supportively,X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain(HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites.Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt,CLEC12Aalt,and C6orf89alt biogenesis,resulting in marked alleviation of its inhibitory effect on B-cell differentiation.Furthermore,we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes.Supportively,shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt,CLEC12Aalt,and C6orf89alt.Conclusions:All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites,catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia. 关键词：Acute lymphoblastic leukemia alternative splicing DUX4/IGH ERG_(alt) RAG1/2

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DNA crosslinking and recombination-activating genes 1/2(RAG1/2)are required for oncogenic splicing in acute lymphoblastic leukemia

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