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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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收录情况： ◇ SCIE

作者：
Hao Zhang[1] ; Nuo Cheng[1] ; Zhihui Li[1] ; Ling Bai[1,7] ; Chengli Fang[2,3] ; Yuwen Li[1] ; Weina Zhang[1] ; Xue Dong[1] ; Minghao Jiang[1] ; Yang Liang[4] ; Sujiang Zhang[1] ; Jianqing Mi[1] ; Jiang Zhu[1] ; Yu Zhang[2,3] ; Sai-Juan Chen[1] ; Yajie Zhao[5,6] ; Xiang-Qin Weng[1] ; Weiguo Hu[1,5,6,*4] ; Zhu Chen[1,*3] ; Jinyan Huang[1,8,9,*2] ; Guoyu Meng[1,*1] ;
机构： [1]Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-JinHospital, 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, SunYat-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：
DOI： 10.1002/cac2.12234
ISSN：

关键词： Acute lymphoblastic leukemia alternative splicing DUX4/IGH ERGalt RAG1/2

摘要：
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.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.We reported previously unrecognized intron retention events in C-type 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 .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.© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

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; SamuelWaxman Cancer Research Foundation
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外文
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出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学
最新[2023]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
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出版当年[2021]版：
Q1 ONCOLOGY
最新[2023]版：
Q1 ONCOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者机构： [1]Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-JinHospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai JiaoTong University, Shanghai 200025, P. R. China
共同第一作者：
通讯作者：
通讯机构： [1]Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-JinHospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai JiaoTong University, Shanghai 200025, 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 [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 [*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]Biomedical Big Data Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, P. R. China. [*3]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 [*4]Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China
推荐引用方式(GB/T 7714)：
Hao Zhang,Nuo Cheng,Zhihui Li,et al.DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia.[J].CANCER COMMUNICATIONS.2021,41(11):1116-1136.doi:10.1002/cac2.12234.
APA：
Hao Zhang,Nuo Cheng,Zhihui Li,Ling Bai,Chengli Fang...&Guoyu Meng.(2021).DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia..CANCER COMMUNICATIONS,41,(11)
MLA：
Hao Zhang,et al."DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia.".CANCER COMMUNICATIONS 41..11(2021):1116-1136

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