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Molecular Medicine

, Volume 17, Issue 11–12, pp 1223–1232 | Cite as

Retroviral Insertional Mutagenesis Can Contribute to Immortalization of Mature T Lymphocytes

  • Sebastian Newrzela
  • Kerstin Cornils
  • Tim Heinrich
  • Julia Schläger
  • Ji-Hee Yi
  • Olga Lysenko
  • Janine Kimpel
  • Boris Fehse
  • Dorothee von Laer
Research Article

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.

Notes

Acknowledgments

The authors would like to thank Marianne Hartmann for technical assistance and Felix Hermann for discussions. This study was supported by the Deutsche Forschungsgemeinschaft (Bonn, Germany; LA1135/9-1 within the SPP1230 and FE568/11-1).

Supplementary material

10020_2011_17111223_MOESM1_ESM.pdf (451 kb)
Supplementary material, approximately 450 KB.

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Sebastian Newrzela
    • 1
  • Kerstin Cornils
    • 2
  • Tim Heinrich
    • 1
  • Julia Schläger
    • 1
  • Ji-Hee Yi
    • 1
  • Olga Lysenko
    • 3
  • Janine Kimpel
    • 4
  • Boris Fehse
    • 2
  • Dorothee von Laer
    • 4
  1. 1.Senckenberg Institute of PathologyGoethe-University Hospital FrankfurtFrankfurt am MainGermany
  2. 2.Interdisciplinary Clinic and Policlinic for Stem Cell Transplantation, Research Department Cell and Gene TherapyUniversity Medical Centre Hamburg-EppendorfHamburgGermany
  3. 3.Institute for Molecular MedicineGoethe-University Hospital FrankfurtFrankfurt am MainGermany
  4. 4.Division for Virology, Institute of VirologyInnsbruck Medical UniversityInnsbruckAustria

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