In the context of gene therapy safety studies in a mouse model, we found that in hematopoietic stem cells high copy numbers of gammaretroviral vectors expressing T-cell oncogenes readily induced T-cell leukemia/lymphoma in recipient mice. However, mature polyclonal T cells could not be transformed (Newrzela et al., Blood 2008).
Yet, and quite surprisingly, T cell receptor (TCR) monoclonal T lymphocytes derived from OT-I mice were transformed with the same kinetics and efficiency as stem cells. This propensity of monoclonal T-cell populations to develop malignancies is highly relevant for evaluating the safety of therapeutic gene transfer into mature T cells, especially the adoptive transfer of therapeutic TCRs. On the other hand, these observations imply that polyclonal T-cell populations can control the outgrowth of malignant T-cell clones. The influence of T-cell repertoire diversity on the clonal dynamics of normal and premalignant T cells will be analyzed. In addition, the molecular mechanisms that control T-cell malignancy in the polyclonal but enhance leukemogenesis in the monoclonal setting will be identified. In addition to defining the risk of T-cell gene therapy, these studies will contribute substantially to our understanding of the pathogenesis of T cell malignancies.

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