title: Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes.
abstract: Several cases of T-cell leukemia caused by gammaretroviral insertional mutagenesis in children treated for x-linked severe combined immunodeficiency (SCID) by transplantation of autologous gene-modified stem cells were reported. In a comparative analysis, we recently showed that mature T cells, on the contrary, are highly resistant to transformation by gammaretroviral gene transfer. In the present study, we observed immortalization of a single T-cell clone in vitro after gammaretroviral transduction of the T-cell protooncogene LMO2. This clone was CD4/CD8 double-negative, but expressed a single rearranged T-cell receptor. The clone was able to overgrow nonmanipulated competitor T-cell populations in vitro, but no tumor formation was observed after transplantation into Rag-1 deficient recipients. The retroviral integration site (RIS) was found to be near the IL2RA and IL15RA genes. As a consequence, both receptors were constitutively upregulated on the RNA and protein level and the immortalized cell clone was highly IL-2 dependent. Ectopic expression of both, the IL2RA chain and LMO2, induced long-term growth in cultured primary T cells. This study demonstrates that insertional mutagenesis can contribute to immortalization of mature T cells, although this is a rare event. Furthermore, the results show that signaling of the IL-2 receptor and the protooncogene LMO2 can act synergistically in maligniant transformation of mature T lymphocytes.
authors.affiliation: Senckenberg Institute of Pathology, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Newrzela
authors.forename: Kerstin
authors.initials: K
authors.lastname: Cornils
authors.forename: Tim
authors.initials: T
authors.lastname: Heinrich
authors.forename: Julia
authors.initials: J
authors.lastname: Schläger
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Olga
authors.initials: O
authors.lastname: Lysenko
authors.forename: Janine
authors.initials: J
authors.lastname: Kimpel
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D060588:LIM Domain Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional / Q000379:methods*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012190:Retroviridae / Q000187:drug effects / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D014161:Transduction, Genetic; D016662:Virus Integration / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D007376:Interleukin-2; D060588:LIM Domain Proteins; C513188:Lmo2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2