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

Abstract 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 a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hao Zhang, Nuo Cheng, Zhihui Li, Ling Bai, Chengli Fang, Yuwen Li, Weina Zhang, Xue Dong, Minghao Jiang, Yang Liang, Sujiang Zhang, Jianqing Mi, Jiang Zhu, Yu Zhang, Sai‐Juan Chen, Yajie Zhao, Xiang‐Qin Weng, Weiguo Hu, Zhu Chen, Jinyan Huang, Guoyu Meng
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Acute lymphoblastic leukemia alternative splicing DUX4/IGH ERGalt RAG1/2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/7fca2b2f3c82432b857e2e6044af3125
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7fca2b2f3c82432b857e2e6044af3125
record_format	dspace
spelling	oai:doaj.org-article:7fca2b2f3c82432b857e2e6044af31252021-11-27T06:05:32ZDNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia2523-354810.1002/cac2.12234https://doaj.org/article/7fca2b2f3c82432b857e2e6044af31252021-11-01T00:00:00Zhttps://doi.org/10.1002/cac2.12234https://doaj.org/toc/2523-3548Abstract 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 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. 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.Hao ZhangNuo ChengZhihui LiLing BaiChengli FangYuwen LiWeina ZhangXue DongMinghao JiangYang LiangSujiang ZhangJianqing MiJiang ZhuYu ZhangSai‐Juan ChenYajie ZhaoXiang‐Qin WengWeiguo HuZhu ChenJinyan HuangGuoyu MengWileyarticleAcute lymphoblastic leukemiaalternative splicingDUX4/IGHERGaltRAG1/2Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Communications, Vol 41, Iss 11, Pp 1116-1136 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acute lymphoblastic leukemia alternative splicing DUX4/IGH ERGalt RAG1/2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Acute lymphoblastic leukemia alternative splicing DUX4/IGH ERGalt RAG1/2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hao Zhang Nuo Cheng Zhihui Li Ling Bai Chengli Fang Yuwen Li Weina Zhang Xue Dong Minghao Jiang Yang Liang Sujiang Zhang Jianqing Mi Jiang Zhu Yu Zhang Sai‐Juan Chen Yajie Zhao Xiang‐Qin Weng Weiguo Hu Zhu Chen Jinyan Huang Guoyu Meng DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
description	Abstract 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 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. 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.
format	article
author	Hao Zhang Nuo Cheng Zhihui Li Ling Bai Chengli Fang Yuwen Li Weina Zhang Xue Dong Minghao Jiang Yang Liang Sujiang Zhang Jianqing Mi Jiang Zhu Yu Zhang Sai‐Juan Chen Yajie Zhao Xiang‐Qin Weng Weiguo Hu Zhu Chen Jinyan Huang Guoyu Meng
author_facet	Hao Zhang Nuo Cheng Zhihui Li Ling Bai Chengli Fang Yuwen Li Weina Zhang Xue Dong Minghao Jiang Yang Liang Sujiang Zhang Jianqing Mi Jiang Zhu Yu Zhang Sai‐Juan Chen Yajie Zhao Xiang‐Qin Weng Weiguo Hu Zhu Chen Jinyan Huang Guoyu Meng
author_sort	Hao Zhang
title	DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
title_short	DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
title_full	DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
title_fullStr	DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
title_full_unstemmed	DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
title_sort	dna crosslinking and recombination‐activating genes 1/2 (rag1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7fca2b2f3c82432b857e2e6044af3125
work_keys_str_mv	AT haozhang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT nuocheng dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT zhihuili dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT lingbai dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT chenglifang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT yuwenli dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT weinazhang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT xuedong dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT minghaojiang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT yangliang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT sujiangzhang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT jianqingmi dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT jiangzhu dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT yuzhang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT saijuanchen dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT yajiezhao dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT xiangqinweng dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT weiguohu dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT zhuchen dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT jinyanhuang dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia AT guoyumeng dnacrosslinkingandrecombinationactivatinggenes12rag12arerequiredforoncogenicsplicinginacutelymphoblasticleukemia
_version_	1718409172748337152

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

Ejemplares similares