LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia
| العنوان: | LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia |
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| المؤلفون: | Ruggero, K, Al-Assar, O, Chambers, J, Codrington, R, Brend, T, Rabbitts, T |
| المصدر: | Leukemia |
| بيانات النشر: | Nature Publishing Group, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Mice, Leukemia, T-Cell, Thymocytes, hemic and lymphatic diseases, Animals, Mice, Transgenic, Genetic Therapy, LIM Domain Proteins, X-Linked Combined Immunodeficiency Diseases, Letter to the Editor, Adaptor Proteins, Signal Transducing, Interleukin Receptor Common gamma Subunit |
| الوصف: | The SCID-X1 disease occurs in males that lack a functional X-linked gene encoding the interleukin 2 receptor subunit gamma (IL2RG) and thus are immuno-deficient (reviewed in Rochman et al.). Gene therapy has been a success in curing SCID-X1 in patients receiving autologous CD34+-bone marrow cells infected with retroviruses expressing IL2RG. This treatment protocol has, however, produced adverse T-cell effects where clonal T-cell leukaemias arose, and four have insertional mutagenesis of the T-cell oncogene LMO2. LMO2 is a T-cell oncogene first discovered via chromosomal translocations in T-cell acute leukaemia (T-ALL) (reviewed in Chambers and Rabbitts). It is unclear if the T-cell neoplasias in the SCID-X1 patients are simply due to insertional activation of the LMO2 gene or reflect synergy between LMO2 and IL2RG. Further, the recurrent involvement of LMO2 in SCID-X1 leukaemias is puzzling as other T-cell oncogenes (for example, TAL1/SCL, HOX11 and LYL1) might equally have been targets. This suggests that specific properties of LMO2 per se are required in these adverse events. The oncogenic potential of IL2RG itself also remains controversial. Although it causes T-cell lymphomas in mice transplanted with virally transduced haematopoetic stem cells, other studies have indicated that IL2RG is not an oncogene. Here we provide evidence that synergy is required between LMO2 and IL2RG proteins specifically in the T-cell lineage to elicit neoplasias and that additional mutations are required such as Notch1 mutations like those in human T-ALL. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1476-5551 0887-6924 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::3565ab3f2d072cdcbd5d232a6e7a915f http://europepmc.org/articles/PMC5227057 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.pmid.dedup....3565ab3f2d072cdcbd5d232a6e7a915f |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765551 08876924 |
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