Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients
Open accessAbstract
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.
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Oncogenic potential is likely highly dependent on context, particularly preexisting genetic aberrations in treated patients.
“However, oncogenic potential is likely highly dependent on context, particularly preexisting genetic aberrations in treated patients [49].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [49]
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- Authors
- Howe, S. J., Mansour, M. R., Schwarzwaelder, K., Bartholomae, C., Hubank, M., Kempski, H., Brugman, M. H., Pike-Overzet, K., Chatters, S. J., de Ridder, D., Gilmour, K. C., Adams, S., Thornhill, S. I., Parsley, K. L., Staal, F. J. T., Gale, R. E., Linch, D. C., Bayford, J., Brown, L., Quaye, M., Kinnon, C., Ancliff, P., Webb, D. K., Schmidt, M., von Kalle, C., Gaspar, H. B., & Thrasher, A. J.
- Affiliations
- University College London (GB)
- German Cancer Research Center (DE)
- Medizinische Hochschule Hannover (DE)
- Great Ormond Street Hospital (GB)
- Erasmus MC (NL)
- Corresponding author
- Thrasher, Adrian J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-09-02
- Volume
- 118
- Issue
- 9
- Pages
- 3143-3150
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2496964
- OpenAlex
- W2057879405
- Cited by
- 1,286
- References
- 2
- Citations by year
- 2026: 33 · 2025: 67 · 2024: 54 · 2023: 61 · 2022: 77 · 2021: 61 · 2020: 60 · 2019: 71 · 2018: 55 · 2017: 65 · 2016: 72 · 2015: 75 · 2014: 79 · 2013: 78 · 2012: 86
- FWCI
- 55.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0507-10370)
- National Institutes of Health
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- X-linked severe combined immunodeficiency, gene therapy, gammaretroviral vectors, insertional mutagenesis, T-cell acute lymphoblastic leukemia, CDKN2A deletion, somatic mutations, leukemogenesis, vector integration
- MeSH terms
- Antineoplastic Agents, DNA-Binding Proteins, Follow-Up Studies, Humans, Infant, Male, Metalloproteins, Models, Biological, Mutation, Proto-Oncogene Proteins, Genetic Therapy, Receptors, Interleukin-2, Mutagenesis, Severe Combined Immunodeficiency, Cyclin-Dependent Kinase Inhibitor p16, Chromosomes, Human, X, Adaptor Proteins, Signal Transducing, Receptor, Notch1, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, LIM Domain Proteins
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