Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1
Open accessAbstract
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [124]
Cites
Physiological Promoters Reduce the Genotoxic Risk of Integrating Gene Vectors
Zychlinski, D., Schambach, A., Modlich, U., Maetzig, T., Meyer, J., Grassman, E., Mishra, A., & Baum, C. (2008) · Molecular Therapy · doi:10.1038/mt.2008.5 · Cited by 271 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Viral vector platforms within the gene therapy landscape
Bulcha, J. T., Wang, Y., Ma, H., Tai, P. W. L., & Gao, G. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00487-6 · Cited by 1,404 · see citing works
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., et al. (2010) · Nature · doi:10.1038/nature09328 · Cited by 1,276 · see citing works
Self-citationLentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
Biffi, A., Montini, E., Lorioli, L., Cesani, M., Fumagalli, F., Plati, T., Baldoli, C., Martino, S., Calabria, A., Canale, S., et al. (2013) · Science · doi:10.1126/science.1233158 · Cited by 1,180 · see citing works
Gene therapy returns to centre stage
Naldini, L. (2015) · Nature · doi:10.1038/nature15818 · Cited by 1,184 · see citing works
Engineered T cells: the promise and challenges of cancer immunotherapy
Fesnak, A. D., June, C. H., & Levine, B. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.97 · Cited by 1,074 · see citing works
Therapeutic in vivo gene transfer for genetic disease using AAV: Progress and challenges
Mingozzi, F., & High, K. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2988 · Cited by 893 · see citing works
Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., Mingozzi, F., Bennicelli, J. L., Ying, G.-S., Rossi, S., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61836-5 · Cited by 865 · see citing works
Gene therapy in a patient with sickle cell disease
Ribeil, J.-A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M., Magrin, E., Caccavelli, L., Neven, B., Bourget, P., El Nemer, W., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1609677 · Cited by 696 · see citing works
Self-citationHematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1700554 · Cited by 604 · see citing works
CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
Cullot, G., Boutin, J., Toutain, J., Prat, F., Pennamen, P., Rooryck, C., Teichmann, M., Rousseau, E., Lamrissi-Garcia, I., Guyonnet-Duperat, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09006-2 · Cited by 474 · see citing works
Lundstrom, K. (2018) · Diseases · doi:10.3390/diseases6020042 · Cited by 469 · see citing works
A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency
Hacein-Bey-Abina, S., Pai, S.-Y., Gaspar, H. B., Armant, M., Berry, C. C., Blanche, S., Bleesing, J., Blondeau, J., de Boer, H., Buckland, K. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1404588 · Cited by 412 · see citing works
Self-citationGenetically Engineered Microvesicles Carrying Suicide mRNA/Protein Inhibit Schwannoma Tumor Growth
Mizrak, A., Bolukbasi, M. F., Ozdener, G. B., Brenner, G. J., Madlener, S., Erkan, E. P., Ströbel, T., Breakefield, X. O., & Saydam, O. (2013) · Molecular Therapy · doi:10.1038/mt.2012.161 · Cited by 337 · see citing works
Wang, J., Exline, C. M., DeClercq, J. J., Llewellyn, G. N., Hayward, S. B., Li, P. W.-L., Shivak, D. A., Surosky, R. T., Gregory, P. D., Holmes, M. C., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3408 · Cited by 261 · see citing works
Schiroli, G., Ferrari, S., Conway, A., Jacob, A., Capo, V., Albano, L., Plati, T., Castiello, M. C., Sanvito, F., Gennery, A. R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aan0820 · Cited by 214 · see citing works
Uncovering and Dissecting the Genotoxicity of Self-inactivating Lentiviral Vectors In Vivo
Cesana, D., Ranzani, M., Volpin, M., Bartholomae, C., Duros, C., Artus, A., Merella, S., Benedicenti, F., Sergi Sergi, L., Sanvito, F., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.3 · Cited by 189 · see citing works
Biosafety Features of Lentiviral Vectors
Schambach, A., Zychlinski, D., Ehrnstroem, B., & Baum, C. (2013) · Human Gene Therapy · doi:10.1089/hum.2012.229 · Cited by 173 · see citing works
Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy
Yilmaz, A., Cui, H., Caligiuri, M. A., & Yu, J. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00998-9 · Cited by 171 · see citing works
Liver-directed lentiviral gene therapy in a dog model of hemophilia B
Cantore, A., Ranzani, M., Bartholomae, C. C., Volpin, M., Valle, P. D., Sanvito, F., Sergi, L. S., Gallina, P., Benedicenti, F., Bellinger, D., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa1405 · Cited by 158 · see citing works
Cartier, N., & Aubourg, P. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2010.00394.x · Cited by 151 · see citing works
Wang, J., DeClercq, J. J., Hayward, S. B., Li, P. W.-L., Shivak, D. A., Gregory, P. D., Lee, G., & Holmes, M. C. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1121 · Cited by 128 · see citing works
Integrase-defective lentiviral vectors: Progress and applications
Banasik, M. B., & McCray, P. B. (2010) · Gene Therapy · doi:10.1038/gt.2009.135 · Cited by 129 · see citing works
Mendell, J. R., Connolly, A. M., Lehman, K. J., Griffin, D. A., Khan, S. Z., Dharia, S. D., Quintana-Gallardo, L., & Rodino-Klapac, L. R. (2022) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2022.02.011 · Cited by 124 · see citing works
Genomic discovery of potent chromatin insulators for human gene therapy
Liu, M., Maurano, M. T., Wang, H., Qi, H., Song, C.-Z., Navas, P. A., Emery, D. W., Stamatoyannopoulos, J. A., & Stamatoyannopoulos, G. (2015) · Nature Biotechnology · doi:10.1038/nbt.3062 · Cited by 121 · see citing works
MLV integration site selection is driven by strong enhancers and active promoters
LaFave, M. C., Varshney, G. K., Gildea, D. E., Wolfsberg, T. G., Baxevanis, A. D., & Burgess, S. M. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1399 · Cited by 114 · see citing works
Enhancers Are Major Targets for Murine Leukemia Virus Vector Integration
De Ravin, S. S., Su, L., Theobald, N., Choi, U., Macpherson, J. L., Poidinger, M., Symonds, G., Pond, S. M., Ferris, A. L., Hughes, S. H., et al. (2014) · Journal of Virology · doi:10.1128/jvi.00011-14 · Cited by 103 · see citing works
Bartus, R. T., & Johnson, E. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.03.027 · Cited by 97 · see citing works
High-efficiency nonviral CRISPR/Cas9-mediated gene editing of human T cells using plasmid donor DNA
Oh, S. A., Senger, K., Madireddi, S., Akhmetzyanova, I., Ishizuka, I. E., Tarighat, S., Lo, J. H., Shaw, D., Haley, B., & Rutz, S. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20211530 · Cited by 88 · see citing works
Treatment of ocular disorders by gene therapy
Solinís, M. Á., del Pozo-Rodríguez, A., Apaolaza, P. S., & Rodríguez-Gascón, A. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2014.12.022 · Cited by 88 · see citing works
Cell and Gene Therapy for the Beta-Thalassemias: Advances and Prospects
Mansilla-Soto, J., Riviere, I., Boulad, F., & Sadelain, M. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.037 · Cited by 83 · see citing works
p12 Tethers the Murine Leukemia Virus Pre-integration Complex to Mitotic Chromosomes
Elis, E., Ehrlich, M., Prizan-Ravid, A., Laham-Karam, N., & Bacharach, E. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1003103 · Cited by 76 · see citing works
Tipanee, J., Samara-Kuko, E., Gevaert, T., Chuah, M. K., & VandenDriessche, T. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.006 · Cited by 76 · see citing works
Brendel, C., Negre, O., Rothe, M., Guda, S., Parsons, G., Harris, C., McGuinness, M., Abriss, D., Tsytsykova, A., Klatt, D., et al. (2020) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.03.015 · Cited by 72 · see citing works
Demeulemeester, J., De Rijck, J., Gijsbers, R., & Debyser, Z. (2015) · BioEssays · doi:10.1002/bies.201500051 · Cited by 71 · see citing works
Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through
Gurumoorthy, N., Nordin, F., Tye, G. J., Wan Kamarul Zaman, W. S., & Ng, M. H. (2022) · Biomedicines · doi:10.3390/biomedicines10010107 · Cited by 69 · see citing works
Gammaretroviral Integration into Nucleosomal Target DNA <i>In Vivo</i>
Roth, S. L., Malani, N., & Bushman, F. D. (2011) · Journal of Virology · doi:10.1128/jvi.00635-11 · Cited by 69 · see citing works
Self-citationRetrovirus and lentivirus vector design and methods of cell conditioning
Cooray, S., Howe, S. J., & Thrasher, A. J. (2012) · Methods in Enzymology · doi:10.1016/b978-0-12-386509-0.00003-x · Cited by 65 · see citing works
Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials
Esensten, J. H., Bluestone, J. A., & Lim, W. A. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100304 · Cited by 62 · see citing works
The old and the new: Prospects for non-integrating lentiviral vector technology
Apolonia, L. (2020) · Viruses · doi:10.3390/v12101103 · Cited by 58 · see citing works
Cas9 protein delivery non-integrating lentiviral vectors for gene correction in sickle cell disease
Uchida, N., Drysdale, C. M., Nassehi, T., Gamer, J., Yapundich, M., DiNicola, J., Shibata, Y., Hinds, M., Gudmundsdottir, B., Haro-Mora, J. J., et al. (2021) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2021.02.022 · Cited by 55 · see citing works
Lentiviral vectors for ocular gene therapy
Arsenijevic, Y., Berger, A., Udry, F., & Kostic, C. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14081605 · Cited by 47 · see citing works
Hu, C., & Lipshutz, G. S. (2012) · Gene Therapy · doi:10.1038/gt.2011.200 · Cited by 48 · see citing works
Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes
Larue, R. C., Plumb, M. R., Crowe, B. L., Shkriabai, N., Sharma, A., DiFiore, J., Malani, N., Aiyer, S. S., Roth, M. J., Bushman, F. D., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku135 · Cited by 44 · see citing works
Self-citationCurative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?
Leonard, A., Tisdale, J., & Abraham, A. (2020) · British Journal of Haematology · doi:10.1111/bjh.16437 · Cited by 45 · see citing works
Development of Gene Therapy for Thalassemia
Nienhuis, A. W., & Persons, D. A. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011833 · Cited by 38 · see citing works
3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes
Babaei, S., Akhtar, W., de Jong, J., Reinders, M., & de Ridder, J. (2015) · Nature Communications · doi:10.1038/ncomms7381 · Cited by 37 · see citing works
Lohia, A., Sahel, D. K., Salman, M., Singh, V., Mariappan, I., Mittal, A., & Chitkara, D. (2022) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2022.02.001 · Cited by 33 · see citing works
Naik, S., Shreya, A. B., Raychaudhuri, R., Pandey, A., Lewis, S. A., Hazarika, M., Bhandary, S. V., Rao, B. S. S., & Mutalik, S. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.118712 · Cited by 33 · see citing works
Blind, J. E., McLeod, E. N., & Campbell, K. J. (2019) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/zxz056 · Cited by 26 · see citing works
Carestia, A., Kim, S.-J., Horling, F., Rottensteiner, H., Lubich, C., Reipert, B. M., Crowe, B. A., & Jenne, C. N. (2021) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.10.023 · Cited by 24 · see citing works
Viral-vector-delivered anti-angiogenic therapies to the eye
Koponen, S., Kokki, E., Kinnunen, K., & Ylä-Herttuala, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020219 · Cited by 24 · see citing works
Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.
Metovic, J., Li, Y., Gong, Y., & Eichler, F. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00443 · Cited by 16 · see citing works
TEG001 Insert Integrity from Vector Producer Cells until Medicinal Product
Straetemans, T., Janssen, A., Jansen, K., Doorn, R., Aarts, T., van Muyden, A. D. D., Simonis, M., Bergboer, J., de Witte, M., Sebestyen, Z., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.11.030 · Cited by 13 · see citing works
Efficient episomal gene transfer to human hepatic cells using the pFAR4–S/MAR vector
Giannakopoulos, A., Quiviger, M., Stavrou, E., Verras, M., Marie, C., Scherman, D., & Athanassiadou, A. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04777-9 · Cited by 10 · see citing works
- Authors
- Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., Clappier, E., Caccavelli, L., Delabesse, E., Beldjord, K., Asnafi, V., MacIntyre, E., Dal Cortivo, L., Radford, I., Brousse, N., Sigaux, F., Moshous, D., Hauer, J., Borkhardt, A., Belohradsky, B. H., Wintergerst, U., Velez, M. C., Leiva, L., Sorensen, R., Wulffraat, N., Blanche, S., Bushman, F. D., Fischer, A., & Cavazzana-Calvo, M.
- Affiliations
- Hôpital Necker-Enfants Malades (FR)
- University of Pennsylvania (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Inserm (FR)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
- Louisiana State University Health Sciences Center New Orleans (US)
- University Medical Center Utrecht (NL)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-09-02
- Volume
- 118
- Issue
- 9
- Pages
- 3132-3142
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2496963
- OpenAlex
- W2107046588
- Cited by
- 1,854
- References
- 1
- Citations by year
- 2026: 55 · 2025: 84 · 2024: 92 · 2023: 79 · 2022: 103 · 2021: 107 · 2020: 89 · 2019: 102 · 2018: 74 · 2017: 101 · 2016: 106 · 2015: 115 · 2014: 124 · 2013: 121 · 2012: 111
- FWCI
- 73.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- University of Pennsylvania
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (T32 AI07634, AI52845, AI66290, U19AI066290, R01AI052845, T32AI007634)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Keywords
- insertional oncogenesis, X-linked SCID, retroviral gene therapy, IL2RG, LMO2, BMI1, cyclin D2, CDKN2A deletion, 6q deletion, T-cell leukemia, chemotherapy response
- MeSH terms
- Proto-Oncogene Mas, Antineoplastic Agents, Chromosome Aberrations, DNA-Binding Proteins, Humans, Infant, Metalloproteins, Models, Biological, Mutation, Proto-Oncogene Proteins, Genetic Therapy, Receptors, Interleukin-2, Leukemia, T-Cell, Cyclins, Severe Combined Immunodeficiency, Gammaretrovirus, Chromosomes, Human, X, Adaptor Proteins, Signal Transducing, Janus Kinase 3, Cyclin D2, LIM Domain Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
