Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells
Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells
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DOI：
10.1182/blood-2005-03-1115
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发表时间：
2005-10-01
期刊：
影响因子：
20.3
通讯作者：
Dunbar, CE
中科院分区：
文献类型：
--
作者：
Calmels, B;Ferguson, C;Dunbar, CE
最近有报道称，基因治疗x连锁严重联合免疫缺陷（X-SCID）后LMO2的插入激活导致了对逆转录病毒载体基因治疗后风险的重新评估。我们分析了7年前用含有标记基因的两性性小鼠白血病病毒（MLV）衍生逆转录病毒载体转导的自体CD34（+）细胞移植的恒河猴的702个整合位点，我们在9只动物中检测到插入到Mds1/Evi1区域的位点共14次。Mds1/Evi1长期稳定整合，主要在髓细胞中。我们假设这种过度表达可能是由于CD34（+）祖细胞在这个特定位点的插入突变对其自我更新和植入潜力的影响。没有证据表明Mds1/Evi1种群正在进行体内克隆扩增，所有动物的血液学正常，没有白血病的证据。在这个相关的临床前模型中，整合位点的表征为基因治疗风险评估以及识别控制造血的基因提供了关键信息。
Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors. In our analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34(+) cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, we detected insertion into one locus, the Mds1/Evi1 region, a total of 14 times in 9 animals. Mds1/Evi1 integrations were observed stably long term, primarily in myeloid cells. We hypothesize that this overrepresentation likely results from an impact on the self-renewal and engraftment potential of CD34(+) progenitor cells via insertional mutagenesis at this specific locus. There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia. Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis.