title: Lymphopoiesis in transgenic mice over-expressing Artemis.
abstract: Artemis is a factor of the non-homologous end joining pathway involved in DNA double-strand break repair that has a critical role in V(D)J recombination. Mutations in DCLRE1C/ARTEMIS gene result in radiosensitive severe combined immunodeficiency in humans owing to a lack of mature T and B cells. Given the known drawbacks of allogeneic hematopoietic stem cell transplantation (HSCT), gene therapy appears as a promising alternative for these patients. However, the safety of an unregulated expression of Artemis has to be established. We developed a transgenic mouse model expressing human Artemis under the control of the strong CMV early enhancer/chicken beta actin promoter through knock-in at the ROSA26 locus to analyze this issue. Transgenic mice present a normal development, maturation and function of T and B cells with no signs of lymphopoietic malignancies for up to 15 months. These results suggest that the over-expression of Artemis in mice (up to 40 times) has no deleterious effects in early and mature lymphoid cells and support the safety of gene therapy as a possible curative treatment for Artemis-deficient patients.
authors.affiliation: Laboratory of Genome Dynamics in the Immune System (DGSI), INSERM UMR1163, Paris, France.|Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Rivera-Munoz
authors.affiliation: Laboratory of Genome Dynamics in the Immune System (DGSI), INSERM UMR1163, Paris, France.|Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Abramowski
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
authors.forename: S
authors.initials: S
authors.lastname: Jacquot
authors.affiliation: Institut Clinique de la Souris, PHENOMIN, CNRS, INSERM, Université de Strasbourg, Illkirch, France.
authors.forename: P
authors.initials: P
authors.lastname: André
authors.affiliation: Généthon, Evry, France.
authors.forename: S
authors.initials: S
authors.lastname: Charrier
authors.affiliation: Service des Animaux Transgéaniques, UPS44, CNRS, Villejuif, France.
authors.forename: K
authors.initials: K
authors.lastname: Lipson-Ruffert
authors.affiliation: Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Unité d'Immunologie et Hématologie Pédiatrique, AP/HP, Hôpital Necker-Enfants Malades, Paris, France.|Collège de France, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Généthon, Evry, France.
authors.forename: A
authors.initials: A
authors.lastname: Galy
authors.affiliation: Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.|Unité d'Immunologie et Hématologie Pédiatrique, AP/HP, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: Laboratory of Genome Dynamics in the Immune System (DGSI), INSERM UMR1163, Paris, France.|Paris-Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: de Villartay
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004720:Endonucleases / Q000235:genetics* / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016511:Severe Combined Immunodeficiency / Q000628:therapy; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C426344:DCLRE1C protein, human; D004720:Endonucleases