期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 118, 期 9, 页码 3143-3150出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI35798
关键词
-
资金
- Wellcome Trust
- United Kingdom Department of Health
- FP6 grant Concerted Safety and Efficacy Evaluation of Retroviral Transgenesis in Gene Therapy of Inherited Diseases [CONSERT 005242]
- Medical Research Council
- Great Ormond Street Hospital National Institutes of Health Biomedical Research Centre
- MRC [G0500389] Funding Source: UKRI
- Great Ormond Street Hospital Childrens Charity [V1223] Funding Source: researchfish
- Medical Research Council [G0500389] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10370] Funding Source: researchfish
X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-beta region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据