Figure 2

The retrospective study by Davé et al. [7] sheds light on the molecular mechanisms behind the formation of leukemias in children in the SCID-X1 trial [1,2]. (a) The precedent for T-cell transformation by co-operation between the Lmo2 and IL-2Rγc proto-oncogenes. The retrospective database search by Davé et al. [7] revealed that a murine leukemia, 98-031, had been previously reported in which two separate retroviral insertions had occurred close to the Lmo2 and IL-2Rγc genes. Insertional mutagenesis effects (gray arrows) from the transcriptional elements of these proviruses probably led to the deregulation of expression of both cellular genes, providing growth-deregulating signals (signals 1 and 2) within the cell. These signals alone were probably insufficient for leukemogenesis, but they may have set up a transforming loop that allowed the infected cell to proliferate more freely than normal [5]. This in turn allowed the accumulation of an unknown number of further genetic mutations that, additively, would provide sufficient additional growth-promoting signals to the infected cell to lead to its complete malignant transformation (signals 3-5, for example). (b) An exactly analogous molecular co-operation is likely to have been responsible for the evolution of the leukemias in the two children in the SCID trial. In this case, the intentional introduction of a retroviral vector encoding the IL-2Rγc gene into the bone-marrow cells of each patient led to integration into (in one patient, shown here), or close to (in a second patient, not shown), the LMO2 locus. As in the precursors to the murine leukemic cells, additional mutations were presumably required in order to accumulate sufficient signals for complete leukemogenesis. For these mutations to occur, the precursor pre-malignant cells would have to undergo multiple cell divisions. The fact that the patients were immune-deficient provided a fertile environment for homeostatic expansion of these cells, allowing them the time and immunological space required to acquire the extra mutations to allow emergence of a leukemic clone, just as demonstrated in the study by Li et al. [8]. Importantly, it was only the findings depicted in (b) that allowed the retrospective analysis shown in (a) to take place. At the time of initiation of the SCID trial, there was no way to predict that the use of the IL-2R3γ therapeutic transgene would lead to the predisposing oncogenic cooperation with the LMO2 gene [5].