Resistance of mature T cells to oncogene transformation
Resistance of mature T cells to oncogene transformation
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DOI：
10.1182/blood-2007-12-128751
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发表时间：
2008-09-15
期刊：
影响因子：
20.3
通讯作者：
von Laer, Dorothee
中科院分区：
文献类型：
--
作者：
Newrzela, Sebastian;Cornils, Kerstin;von Laer, Dorothee
干细胞基因转移后逆转录病毒插入突变引起的白血病已在几种实验动物和X连锁严重联合免疫缺陷病治疗的患者中报道。在这里，我们分析了基因转移到成熟T细胞是否具有相同的遗传毒性风险。为了在实验“最坏情况”中解决这个问题，我们用高拷贝数的γ逆转录病毒载体转导来自C57 BL/6（Ly5.1）供体小鼠的成熟T细胞和造血祖细胞，所述γ逆转录病毒载体编码强效T细胞癌基因LMO 2、TCL 1或Delta TrkA（TrkA的组成型活性突变体）。在移植到RAG-1缺陷受体（Ly5.2）中后，接受干细胞移植的动物对于具有特征表型的所有研究的癌基因并且在特征潜伏期后发展为T细胞淋巴瘤/白血病。连接介导的聚合酶链反应分析显示恶性肿瘤的单克隆性或寡克隆性。与此形成鲜明对比的是，接受相同载体转导的T细胞移植的小鼠中没有一只发生白血病/淋巴瘤，尽管基因修饰的细胞持续存在。因此，我们的数据提供了直接的证据，成熟的T细胞比造血祖细胞更不容易转化。
Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or Delta TrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1 deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received T-cell transplants transduced with the same vectors developed leukemia/lymphoma despite persistence of genemodified cells. Thus, our data provide direct evidence that mature T cells are less prone to transformation than hematopoietic progenitor cells.