Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes.
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Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes. / Newrzela, Sebastian; Cornils, Kerstin; Heinrich, Tim; Schläger, Julia; Yi, Ji-Hee; Lysenko, Olga; Kimpel, Janine; Fehse, Boris; Dorothee, Von Laer.
in: MOL MED, Jahrgang 17, Nr. 11-12, 11-12, 2011, S. 1223-1232.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes.
AU - Newrzela, Sebastian
AU - Cornils, Kerstin
AU - Heinrich, Tim
AU - Schläger, Julia
AU - Yi, Ji-Hee
AU - Lysenko, Olga
AU - Kimpel, Janine
AU - Fehse, Boris
AU - Dorothee, Von Laer
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
U2 - 10.2119/molmed.2010.00193
DO - 10.2119/molmed.2010.00193
M3 - SCORING: Journal article
VL - 17
SP - 1223
EP - 1232
JO - MOL MED
JF - MOL MED
SN - 1076-1551
IS - 11-12
M1 - 11-12
ER -