BCR-ABL1–positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia
BCR-ABL1–positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia
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DOI：
10.1038/leu.2014.51
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发表时间：
2014-01
期刊：
影响因子：
11.4
通讯作者：
Xiaojian Zhu;Yong You;Qiubai Li;Chen Zeng;Fen-fen Fu;An-Yuan Guo;H. Zhang;P. Zou;Z. Zhong;Hongxiang Wang;Yaohui Wu;Fancong Kong;Zhichao Chen
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文献类型：
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作者：
Xiaojian Zhu;Yong You;Qiubai Li;Chen Zeng;Fen-fen Fu;An-Yuan Guo;H. Zhang;P. Zou;Z. Zhong;Hongxiang Wang;Yaohui Wu;Fancong Kong;Zhichao Chen
残余白血病细胞诱导正常造血移植物恶性转化被认为是供者细胞白血病（DCL）的关键机制。白血病细胞衍生的微泡（MV）在这种转化的影响进行了检查。我们发现K562白血病细胞来源的MV中含有断点簇区域-Abelson白血病基因人类同源物1（BCR-ABL 1）mRNA。与BCR-ABL 1阳性MV孵育后，来自正常移植物的单核细胞在体外和体内均表现出白血病样恶性表型。BCR-ABL 1 mRNA从MV水平转移到受体细胞是转化的关键。观察到相对基因组不稳定性，并认为这是受体细胞中的主要机制。MV通过两种不同的途径导致基因组不稳定：通过随后的激活诱导的胞苷脱氨酶和活性氧的过度表达，介导DNA断裂和重组;以及通过上调甲基转移酶和全球DNA超甲基化。我们证明BCR-ABL 1阳性MV可以通过基因组不稳定性启动正常造血移植物的恶性转化，这可能是一个方便和可操作的模型，用于研究白血病，特别是DCL的发生。此外，MV本身可以作为一个早期预警指标和新的工具，以检测和预防DCL的发生。
Malignant transformation of normal hematopoietic transplants induced by residual leukemia cells is considered as a pivotal mechanism of donor cell leukemia (DCL). The effects of leukemia cell–derived microvesicles (MVs) in this transformation were examined. We found that MVs derived from K562 leukemia cells contained the breakpoint cluster region–Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA. Following incubation with BCR-ABL1–positive MVs, mononuclear cells derived from normal transplants exhibited a leukemia-like malignant phenotype both in vitro and in vivo. Horizontal transfer of BCR-ABL1 mRNA from MVs into the recipient cells was critical to the transformation. Relative genomic instability was observed and considered the main mechanism in the recipient cells. MVs contributed to genomic instability by two distinct pathways: via consequent overexpression of activation-induced cytidine deaminase and reactive oxygen species, which mediated DNA breakage and recombination; and via upregulation of methyltransferases and global DNA hypermethylation. We demonstrated that BCR-ABL1–positive MVs could initiate malignant transformation of normal hematopoietic transplants through genomic instability, which might serve as a convenient and operable model for investigating leukemogenesis, especially for DCL. Furthermore, MVs themselves could act as an early warning indicator and a novel tool to detect and prevent the occurrence of DCL.