LMO2 -Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
Abstract
We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as γ chain (γc) deficiency] in 9 out of 10 patients by retrovirus-mediated γc gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with γδ+ or αβ+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2 . Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
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SCID-X1 patients who received HSCs transduced with murine leukaemia virus developed abnormal T cell proliferation due to insertion of a retroviral vector near the LMO2 proto-oncogene.
“For example, SCID-X1 patients who received HSCs transduced with murine leukaemia virus (MLV) developed abnormal T cell proliferation due to the insertion of a retroviral vector near the LMO2 proto-oncogene [123,124].”
From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [123]
Integration of proviral DNA can disrupt or enhance expression of host genes, resulting in altered and sometimes fatal outcomes.
“Equally consequential is the integration of the proviral DNA for the host, since it can either disrupt or enhance the expression of the host genes, resulting in altered and sometimes even fatal outcomes (Hacein-Bey-Abina et al. 2003, Bushman 2007, Montini et al. 2009, Desfarges and Ciuffi 2012).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Hacein-Bey-Abina et al. 2003
Lentiviral vectors are considered safer than gamma-retroviral vectors in terms of their semi-random integration patterns, as gene integration does not preferentially occur in start regions of active genes.
“Lentiviral vectors are considered safer than gamma-retroviral vectors in terms of their semi-random integration patterns, as gene integration does not preferentially occur in start regions of active genes (93-95).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [94]
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Genetic Modification of the Lung Directed Toward Treatment of Human Disease
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The Safety of Embryonic Stem Cell Therapy Relies on Teratoma Removal
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Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
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“…consequential is the integration of the proviral DNA for the host, since it can either disrupt or enhance the expression of the host genes, resulting in altered and some-times even fatal outcomes (Hacein-Bey-Abina et al. 2003 , Bush-man 2007 , Montini et al. 2009 , Desfarges and Ciuffi 2012 ).”
- Authors
- Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M. P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C. S., Pawliuk, R., Morillon, E., Sorensen, R., Forster, A., Fraser, P., Cohen, J. I., de Saint Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., Stoppa-Lyonnet, D., Romana, S., Radford-Weiss, I., Gross, F., Valensi, F., Delabesse, E., Macintyre, E., Sigaux, F., Soulier, J., Leiva, L. E., Wissler, M., Prinz, C., Rabbitts, T. H., Le Deist, F., Fischer, A., & Cavazzana-Calvo, M.
- Affiliations
- INSERM Unit 429, Cedex 15, France.
- Hôpital Necker-Enfants Malades (FR)
- Brigham and Women's Hospital (US)
- Louisiana State University (US)
- Corresponding author
- Fischer, A.
- ORCID
- Venue
- Science
- Published
- 2003-10-17
- Volume
- 302
- Issue
- 5644
- Pages
- 415-419
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2137440275
- Cited by
- 3,587
- References
- 2
- Citations by year
- 2026: 56 · 2025: 87 · 2024: 95 · 2023: 84 · 2022: 96 · 2021: 83 · 2020: 109 · 2019: 98 · 2018: 100 · 2017: 123 · 2016: 139 · 2015: 149 · 2014: 163 · 2013: 180 · 2012: 182
- FWCI
- 120.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- DigitalGeorgetown (Georgetown University Library) (submittedVersion)
- 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 › Surgery › Xenotransplantation and immune response
- Keywords
- LMO2, X-linked severe combined immunodeficiency, retroviral integration, T cell clonal expansion, gene therapy, γδ T cells, alpha beta T cells, retroviral gene transfer, CD34+ bone marrow cells, gammaretrovirus
- MeSH terms
- Proto-Oncogene Mas, Clinical Trials as Topic, Clone Cells, DNA-Binding Proteins, Gene Expression Regulation, Genetic Vectors, Hematopoietic Stem Cells, Humans, Infant, Metalloproteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogenes, Retroviridae, T-Lymphocytes, Transcription, Genetic, Virus Replication, Genetic Therapy, Receptors, Interleukin-2, Leukemia-Lymphoma, Adult T-Cell, Mutagenesis, Insertional, Severe Combined Immunodeficiency, Virus Integration, Gene Transfer Techniques, Hematopoietic Stem Cell Transplantation, Adaptor Proteins, Signal Transducing, LIM Domain Proteins
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