ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
Cell-intrinsic and vector-related properties cooperate to determine the incidence and consequences of insertional mutagenesis.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 65 citations in OpenAlex.
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- The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma.Cellular immunology · 2019Review
- Barcoding of Macaque Hematopoietic Stem and Progenitor Cells: A Robust Platform to Assess Vector Genotoxicity.Molecular therapy. Methods & clinical development · 2018Article
- TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis.Scientific reports · 2017Article
- Multimodal Lentiviral Vectors for Pharmacologically Controlled Switching Between Constitutive Single Gene Expression and Tetracycline-Regulated Multiple Gene Collaboration.Human gene therapy methods · 2017Article
- Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion.Molecular cancer · 2017Article
- INSPIIRED: A Pipeline for Quantitative Analysis of Sites of New DNA Integration in Cellular Genomes.Molecular therapy. Methods & clinical development · 2017Article
- Safe and Efficient Gene Therapy for Pyruvate Kinase Deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy.Journal of the National Cancer Institute · 2016Review
- Towards a Safer, More Randomized Lentiviral Vector Integration Profile Exploring Artificial LEDGF Chimeras.PloS one · 2016Article
- A comparison of foamy and lentiviral vector genotoxicity in SCID-repopulating cells shows foamy vectors are less prone to clonal dominance.Molecular therapy. Methods & clinical development · 2016Article
- High-throughput screening identifies compounds that enhance lentiviral transduction.Gene therapy · 2014Article
- Clonal Dominance With Retroviral Vector Insertions Near the ANGPT1 and ANGPT2 Genes in a Human Xenotransplant Mouse Model.Molecular therapy. Nucleic acids · 2014Article
- Dual-regulated lentiviral vector for gene therapy of X-linked chronic granulomatosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- S/MAR sequence confers long-term mitotic stability on non-integrating lentiviral vector episomes without selection.Nucleic acids research · 2014Article
- Ectopic expression of HOXC6 blocks myeloid differentiation and predisposes to malignant transformation.Experimental hematology · 2014Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In gene therapeutic approaches targeting hematopoietic cells, insertional mutagenesis may provoke clonal dominance with potential progress to overt leukemia. To investigate the contribution of cell-intrinsic features and determine the frequency of insertional proto-oncogene activation, we sorted hematopoietic subpopulations before transduction with replication-deficient gamma-retroviral vectors and studied the clonal repertoire in transplanted C57BL/6J mice. Progressive clonal dominance only developed in the progeny of populations with intrinsic stem cell potential, where expanding clones with insertional upregulation of proto-oncogenes such as Evi1 were retrieved with a frequency of approximately 10(-4). Longitudinal studies by high-throughput sequencing and locus-specific quantitative PCR showed clones with >50-fold expansion between weeks 5 and 31 after transplantation. In contrast, insertional events in proto-oncogenes did not endow the progeny of multipotent or myeloid-restricted progenitors with the potential for clonal dominance (risk <10(-6)). Transducing sorted hematopoietic stem cells (HSCs) with self-inactivating (SIN) lentiviral vectors in short-term cultures improved chimerism, and although clonal dominance developed, there was no evidence for insertional events in the vicinity of proto-oncogenes as the underlying cause. We conclude that cell-intrinsic properties cooperate with vector-related features to determine the incidence and consequences of insertional mutagenesis. Furthermore, our study offers perspectives for refinement of animal experiments in the assessment of vector-related genotoxicity.
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