Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell.
Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell.
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根据靶细胞的基因表达和染色质构象，基因治疗患者中逆转录病毒载体的整合特征是细胞特异性的。
DOI：
10.1002/emmm.201000108
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发表时间：
2011-02
影响因子：
11.1
通讯作者：
Aiuti, Alessandro
中科院分区：
文献类型：
--
作者：
Biasco, Luca;Ambrosi, Alessandro;Pellin, Danilo;Bartholomae, Cynthia;Brigida, Immacolata;Roncarolo, Maria Grazia;Di Serio, Clelia;von Kalle, Christof;Schmidt, Manfred;Aiuti, Alessandro
逆转录病毒载体的基因组分布分析是监测基因治疗(GT)试验中“载体-宿主”效应的有力工具，也提供了基于靶细胞遗传和表观遗传状态的“宿主-载体”影响的关键信息。我们有独特的机会比较了相同的治疗性Moloney小鼠白血病病毒(MLV)载体在腺苷脱氨酶-严重联合免疫缺陷(ADA-SCID)遗传背景下的插入情况，在两个基于输注转导的成熟淋巴细胞(外周血淋巴细胞，PBL)或单一输注造血干/祖细胞(HSC)的GT试验中。我们发现，根据靶细胞的差异表达谱，载体插入是细胞特异性的，在PBL-GT中，与HSC-GT不同，载体插入有利于参与免疫系统和T细胞功能/途径的基因以及T细胞DNA酶敏感部位。染色质构象和组蛋白修饰影响整合偏好，但我们发现只有H3K27me3是细胞特异性的不受欢迎的，因此代表了细胞类型依赖的插入分布的关键表观遗传决定因素。我们的研究表明，根据GT后几年患者体内和体外靶细胞的遗传/染色质状态，MLV载体插入轮廓是细胞特异性的。
The analysis of genomic distribution of retroviral vectors is a powerful tool to monitor ‘vector-on-host’ effects in gene therapy (GT) trials but also provides crucial information about ‘host-on-vector’ influences based on the target cell genetic and epigenetic state. We had the unique occasion to compare the insertional profile of the same therapeutic moloney murine leukemia virus (MLV) vector in the context of the adenosine deaminase-severe combined immunodeficiency (ADA-SCID) genetic background in two GT trials based on infusions of transduced mature lymphocytes (peripheral blood lymphocytes, PBL) or a single infusion of haematopoietic stem/progenitor cells (HSC). We found that vector insertions are cell-specific according to the differential expression profile of target cells, favouring, in PBL-GT, genes involved in immune system and T-cell functions/pathways as well as T-cell DNase hypersensitive sites, differently from HSC-GT. Chromatin conformations and histone modifications influenced integration preferences but we discovered that only H3K27me3 was cell-specifically disfavoured, thus representing a key epigenetic determinant of cell-type dependent insertion distribution. Our study shows that MLV vector insertional profile is cell-specific according to the genetic/chromatin state of the target cell both in vitro and in vivo in patients several years after GT.
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逆转录病毒DNA整合：靶位点选择的病毒和细胞决定因素。
影响因子：
6.7
作者：
Lewinski, Mary K;Yamashita, Masahiro;Emerman, Michael;Ciuffi, Angela;Marshall, Heather;Crawford, Gregory;Collins, Francis;Shinn, Paul;Leipzig, Jeremy;Hannenhalli, Sridhar;Berry, Charles C;Ecker, Joseph R;Bushman, Frederic D
通讯作者：
Bushman, Frederic D
影响因子：
23.9
作者：
Cui K;Zang C;Roh TY;Schones DE;Childs RW;Peng W;Zhao K
通讯作者：
Zhao K
影响因子：
20.3
作者：
Maes, Jerome;Maleszewska, Marta;Goodhardt, Michele
通讯作者：
Goodhardt, Michele
影响因子：
15.9
作者：
Deichmann, Annette;Hacein-Bey-Abina, Salima;Cavazzana-Calvo, Marina
通讯作者：
Cavazzana-Calvo, Marina
影响因子：
20.3
作者：
Kustikova, Olga S.;Geiger, Hartmut;Baum, Christopher
通讯作者：
Baum, Christopher