ArticleMolecular therapy : the journal of the American Society of Gene Therapy2012
Lentiviral vector induced insertional haploinsufficiency of Ebf1 causes murine leukemia.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 60 citations in OpenAlex.
- Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency.Nature communications · 2022Trial
- Review
- Interlaboratory assessment of candidate reference materials for lentiviral vector copy number and integration site measurements.Molecular therapy. Methods & clinical development · 2025Article
- TGFCells · 2023Article
- Review
- Enhanced Transduction of Human Hematopoietic Stem Cells by AAV6 Vectors: Implications in Gene Therapy and Genome Editing.Molecular therapy. Nucleic acids · 2020Article
- Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice.Molecular therapy. Methods & clinical development · 2018Article
- Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis.Leukemia · 2018Article
- Steerable Induction of the Thymosin β4/MRTF-A Pathway via AAV-Based Overexpression Induces Therapeutic Neovascularization.Human gene therapy · 2017Article
- Development of the First World Health Organization Lentiviral Vector Standard: Toward the Production Control and Standardization of Lentivirus-Based Gene Therapy Products.Human gene therapy methods · 2017Article
- Multimodal Lentiviral Vectors for Pharmacologically Controlled Switching Between Constitutive Single Gene Expression and Tetracycline-Regulated Multiple Gene Collaboration.Human gene therapy methods · 2017Article
- De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.American journal of human genetics · 2017Article
- NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.PloS one · 2016Article
- ZNF423 and ZNF521: EBF1 Antagonists of Potential Relevance in B-Lymphoid Malignancies.BioMed research international · 2015Review
- Alpharetroviral vectors: from a cancer-causing agent to a useful tool for human gene therapy.Viruses · 2014Review
- Data vs. dogma: HIV-1 integrations driving clonal selection.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Long-term tracking of segmental bone healing mediated by genetically engineered adipose-derived stem cells: focuses on bone remodeling and potential side effects.Tissue engineering. Part A · 2014Article
- Decitabine suspends human CD34+ cell differentiation and proliferation during lentiviral transduction.PloS one · 2014Article
- Cancer gene discovery: exploiting insertional mutagenesis.Molecular cancer research : MCR · 2013Review
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Integrating vectors developed on the basis of various retroviruses have demonstrated therapeutic potential following genetic modification of long-lived hematopoietic stem and progenitor cells. Lentiviral vectors (LV) are assumed to circumvent genotoxic events previously observed with γ-retroviral vectors, due to their integration bias to transcription units in comparison to the γ-retroviral preference for promoter regions and CpG islands. However, recently several studies have revealed the potential for gene activation by LV insertions. Here, we report a murine acute B-lymphoblastic leukemia (B-ALL) triggered by insertional gene inactivation. LV integration occurred into the 8th intron of Ebf1, a major regulator of B-lymphopoiesis. Various aberrant splice variants could be detected that involved splice donor and acceptor sites of the lentiviral construct, inducing downregulation of Ebf1 full-length message. The transcriptome signature was compatible with loss of this major determinant of B-cell differentiation, with partial acquisition of myeloid markers, including Csf1r (macrophage colony-stimulating factor (M-CSF) receptor). This was accompanied by receptor phosphorylation and STAT5 activation, both most likely contributing to leukemic progression. Our results highlight the risk of intragenic vector integration to initiate leukemia by inducing haploinsufficiency of a tumor suppressor gene. We propose to address this risk in future vector design.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.