Abstract 3309: T cell lymphoblastic leukemia in survivin TCR transgenic mice.

Abstract

Abstract Survivin has been considered a potential tumor antigen due to high expression in most cancers and limited expression in normal tissues. To explore whether survivin reactive TCRs mediate antitumor effects in mice, we generated TCR transgenic (Tg) mice with specificity for the H-2b restricted immunodominant epitope of survivin. Survivin reactive T cells were CD8+ and mediated immune reactivity toward survivin peptide pulsed targets. Some antitumor reactivity was observed, but it was not potent, and the survivin TCR Tg+ cells did not mediate objective tumor regression of survivin bearing tumors. Surprisingly, spontaneous T cell acute lymphoblastic leukemia (T-ALL) was observed beginning at 4-6 months of age in Tg+Rag+/- and Tg+Rag-/- mice. By one year of age, all survivin Tg+ mice succumbed to T-cell ALL. The leukemic cells were CD3+, survivin TCR+, and CD8+ or CD4-/CD8-Occurrence in 3 founders suggests that the transgene itself, rather than insertional mutagenesis, is causative. Given that survivin is expressed in the thymus, we postulated that the TCR-Tg serves as an oncogene via recognition of survivin peptides, which expands early thymic progenitors. In support of this, premalignant survivin TCR Tg+ thymi show expanded CD4-CD8-CD44-CD25- thymocytes and increased BrdU incorporation and leukemia incidence was significantly diminished TCR-Tg+β2m-/- mice. Subsequent to expansion of early thymic progenitors in response to TCR triggering, survivin TCR Tg+ cells acquire NOTCH mutations and upregulate CD25, implicating NOTCH signaling as a 2nd hit in this oncogenic process. At least one NOTCH1 mutation was found in all leukemias, with PEST (8/8), 5’ deletions (19/25) and heterodimerization mutations observed. T-ALL with NOTCH mutations was also observed at reduced frequencies, in TCR Tg mice with specificity to WT1 and gp100. We conclude that genetic engineering aimed at endowing hematopoietic or T lymphoid progenitors with the capacity to recognize tumor antigens expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis. Citation Format: Yongzhi Cui, Masahiro Onozawa, Haiying Qin, Terry Fry, Peter Aplan, Crystal L. Mackall. T cell lymphoblastic leukemia in survivin TCR transgenic mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3309. doi:10.1158/1538-7445.AM2013-3309 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.