DNA transposon mechanisms and pathways of genotoxicity.
DNA transposon mechanisms and pathways of genotoxicity.
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DNA转座子基因毒性机制和途径。
DOI：
10.1016/j.ymthe.2023.01.023
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Bushman,FredericD
中科院分区：
文献类型：
--
作者：
Bushman,FredericD
最近，嵌合抗原受体 (CAR) T 癌症治疗试验（CARTELL 研究）1、2 报告了两种淋巴瘤，其中使用piggyBac DNA 转座子将工程化受体基因传递至人类 T 细胞。研究发现，转化细胞含有多个整合的转座子 DNA 拷贝（每个细胞 4-24 个），并且细胞染色体 DNA 中存在多个重排。多种因素可能促成转化，包括载体设计和细胞处理方面。 1, 2 在评估可能的转化机制时，考虑与更熟悉的逆转录病毒整合不同的转座特性可能会有所帮助，并询问这些特性是否会影响两种淋巴瘤的发展。例如，整合到宿主染色体中的转座子 DNA 可以作为进一步几轮切除和转座的底物，其中每次切除事件都会在空的转座子供体位点处产生 DNA 双链断裂。转座酶还可以直接在染色体序列上切割基因组 DNA，这些序列偶然类似于转座酶结合位点。下面更全面地描述了这些机制，并描述了其他实验，这些实验可以帮助阐明基因毒性的可能途径并潜在地降低风险。使用 DNA 转座子 3 进行基因添加比逆转录病毒递送具有绕过载体颗粒生成步骤的优点，因此使用起来可能更简单且更便宜。然而，最近在一项用于治疗 B 细胞恶性肿瘤的 CAR T 试验中，在 Piggybac 递送后发现了两例淋巴瘤，1, 2 并且转化的细胞含有多个整合的转座子和染色体重排。作者认为，插入突变并不是这两种情况的一个因素，尽管这两种不良事件产生的转化细胞都含有整合素。
Recently two lymphomas were reported in a chimeric antigen receptor (CAR) T cancer therapy trial (the CARTELL study) 1, 2 in which the piggyBac DNA transposon was used to deliver an engineered receptor gene to human T cells. The transformed cells were found to contain multiple integrated transposon DNA copies (4–24 per cell) and harbor multiple rearrangements in cellular chromosomal DNA. A variety of factors may have contributed to transformation, including aspects of the vector design and cell processing. 1, 2 In evaluating possible mechanisms of transformation, it may be useful to consider the properties of transposition that differ from the more familiar retroviral integration and ask whether these could have influenced development of the two lymphomas. For example, transposon DNA integrated in a host chromosome can be a substrate for further rounds of excision and transposition, where each excision event generates a DNA double-strand break at the empty transposon-donor site. Transposases can also cleave genomic DNA directly at chromosomal sequences that, by chance, resemble transposase-binding sites. These mechanisms are described more fully below, and additional experiments are described that could help clarify possible pathways of genotoxicity and potentially mitigate risks.Use of DNA transposons 3 for gene addition has the advantage over retroviral delivery of bypassing the step of vector particle generation and so may be simpler and less expensive to use. However, recently two cases of lymphoma were found in a CAR T trial to treat B cell malignancies following piggybac delivery, 1, 2 and the transformed cells contained multiple integrated transposons and chromosomal rearrangements. The authors suggested that insertional mutagenesis was not a factor in the two cases, though transformed cells from both adverse events harbored integra-
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影响因子：
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作者：
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DOI：
--
发表时间：
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期刊：
影响因子：
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作者：
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