These transgenic mice express a T cell receptor (TCR) recognizing an immunodominant epitope of mouse Survivin (Sur20-28, a tumor-associated antigen (TAA)) during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) is reported to occur in 100% of Sur-TCR-Tg mice beginning at 4 months of age. T-ALL in Sur-TCR-Tg mice is characterized by enlargement of the spleen, thymus, lymph nodes, lung, liver, and kidney due to infiltration with sheets of terminal deoxynucleotidyl transferase (TdT)+ blasts. No phenotypic differences have been observed between hemizygotes and homozygotes. Both male and female transgenic mice are fertile. The transgene was integrated on mouse Chromosome 11, but copy number has not been determined.
The process of leukemogenesis observed in this model shows similarities with several other animal models of T-ALL, as well as T-ALL observed in patients treated with IL2Rγc-based gene therapy. In both this model and the clinical experience with IL2Rγc retroviral-based gene therapy, a receptor capable of providing a potent activation stimulus was expressed during the early stages of thymopoiesis and in both cases NOTCH1 mutations cooperated to generate full transformation. Although the issue of whether IL2Rγc expressed during early thymopoiesis can provide a leukemogenic signal is unresolved, several animal models have implicated the TCR as an oncogene in T-ALL. In some cases, TCR signaling during early thymopoiesis appears sufficient to induce T-ALL, whereas in others the TCR signals play a cooperating role as part of an oncogenic cascade. Pre-TCR signaling has also been implicated in T-ALL development as a cooperating event.
