A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of γC gene oncogenicity

The emergence of leukemia following gene transfer torestore common cytokine receptor γ chain (γC) function in X-linked severe combined immunodeficiency(SCID-X1) has raised important questions with respect togene therapy safety. To explore the risk factors involved,we tested the oncogenic potential of human γC in newstrains of transgenic mice expressing the gene under thecontrol of the CD2 promoter and locus control region(LCR). These mice demonstrated mildly perturbed T-celldevelopment, with an increased proportion of thymicCD8 cells, but showed no predisposition to tumor development even on highly tumor prone backgrounds orafter γ-retrovirus infection. The human CD2-γC transgene rescued T and B-cell development in γC−/− micebut with an age-related delay, mimicking postnatalreconstitution in SCID-X1 gene therapy subjects. However, we noted that γC−/− mice are acutely susceptibleto murine leukemia virus (MLV) leukemogenesis, andthat this trait was not corrected by the γC transgene. Weconclude that the SCID-X1 phenotype can be correctedsafely by stable ectopic expression of γC and that thetransgene is not significantly oncogenic when expressedin this context. However, an underlying predisposition conferred by the SCID-X1 background appears tocollaborate with insertional mutagenesis to increase therisk of tumor development.