Gene therapy: is IL2RG oncogenic in T-cell development?
The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2.
Pike-Overzet
Karin
K
Department of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
de Ridder
Dick
D
Weerkamp
Floor
F
Baert
Miranda R M
MR
Verstegen
Monique M
MM
Brugman
Martijn H
MH
Howe
Steven J
SJ
Reinders
Marcel J T
MJ
Thrasher
Adrian J
AJ
Wagemaker
Gerard
G
van Dongen
Jacques J M
JJ
Staal
Frank J T
FJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000009:adverse effects*; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2