Ectopic retroviral expression of LMO2, but not IL2Rγ, blocks human T-cell development from CD34+cells:: implications for leukemogenesis in gene therapy
Ectopic retroviral expression of LMO2, but not IL2Rγ, blocks human T-cell development from CD34+cells:: implications for leukemogenesis in gene therapy
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DOI：
10.1038/sj.leu.2404563
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发表时间：
2007-04-01
期刊：
影响因子：
11.4
通讯作者：
Staal, F. J. T.
中科院分区：
文献类型：
--
作者：
Pike-Overzet, K.;de Ridder, D.;Staal, F. J. T.
在SCID-X1的基因治疗试验中白血病的发生突出了插入突变作为一种不良反应。虽然逆转录病毒整合在T细胞急性淋巴细胞白血病（T-ALL）癌基因LIM-only蛋白2（LMO 2）附近似乎是一种常见的事件，但目前还不清楚为什么LMO 2被优先靶向。我们发现，经典的T-ALL癌基因，LMO 2是最高的转录在CD 34+祖细胞。在用基因治疗方案中通常使用的生长因子刺激后，LMO 2、LYL 1、TAL 1和TAN 1的转录是最显著的。因此，这些癌基因可能易受病毒整合的影响。在SCID-X1中突变的白细胞介素-2受体γ链（IL 2 R γ）已被认为是LMO 2的协同致癌基因。然而，我们发现过表达IL 2 R γ对T细胞发育没有影响。相反，逆转录病毒过表达的LMO 2在CD 34+细胞中引起T细胞发育严重异常，但B细胞和骨髓发育不受影响。我们的数据有助于解释为什么LMO 2优先于许多其他已知的T-ALL癌基因。此外，在T细胞发育过程中，逆转录病毒介导的IL 2 R γ表达可能不是直接致癌的。相反，正常IL 7受体信号传导的恢复可能允许T细胞发育进展到异位LMO 2表达导致异常胸腺细胞生长的阶段。
The occurrence of leukemia in a gene therapy trial for SCID-X1 has highlighted insertional mutagenesis as an adverse effect. Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially targeted. We show that of classical T-ALL oncogenes, LMO2 is most highly transcribed in CD34+ progenitor cells. Upon stimulation with growth factors typically used in gene therapy protocols transcription of LMO2, LYL1, TAL1 and TAN1 is most prominent. Therefore, these oncogenes may be susceptible to viral integration. The interleukin-2 receptor gamma chain (IL2R gamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2. However, we found that overexpressing IL2R gamma had no effect on T-cell development. In contrast, retroviral overexpression of LMO2 in CD34+ cells caused severe abnormalities in T-cell development, but B-cell and myeloid development remained unaffected. Our data help explain why LMO2 was preferentially targeted over many of the other known T-ALL oncogenes. Furthermore, during T-cell development retrovirus-mediated expression of IL2R gamma may not be directly oncogenic. Instead, restoration of normal IL7-receptor signaling may allow progression of T-cell development to stages where ectopic LMO2 expression causes aberrant thymocyte growth.