Abstract 3072: Characterization of TCL1-Tg:p53-/- mice that resemble human chronic lymphocytic leukemia with 17p-deletion: alterations in p53→Mir30→EZH2 axis.

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. CLL patients with deletion of chromosome 17p, where the tumor suppressor p53 gene is located, often develop a more aggressive disease with poor clinical outcomes. However, the underlying mechanism remains unclear. We have recently generated mice with Eμ-Tcl1-Tg:p53-/- genotype and showed that these mice develop aggressive leukemia that resembles human CLL with 17p deletion. In the present study, we further demonstrated that the p53 deficiency in the Tcl1 transgenic mice resulted in significant down-regulation of microRNAs miR-15a and miR16-1, associated with a substantial up-regulation of Mcl-1, suggesting that the p53-miR15a/16-Mcl-1 axis may play an important role in CLL pathogenesis. Interestingly, we also found that loss of p53 resulted in a significant decrease in expression of the miR-30 family in leukemia lymphocytes from the Eμ-Tcl1-Tg:p53-/- mice. Consistently, primary leukemia cells from CLL patients with 17p deletion also showed a decrease in the miR-30d expression. To further exam the biological significance of decrease in the miR-30 family in CLL, we investigated the potential involvement of EZH2 (enhancer of zeste homolog 2), a component of the Polycomb repressive complex known to be a downstream target of miR-30d and plays a role in disease progression in several solid cancers. RT-PCR and western blot analyses showed that both EZH2 mRNA transcript and protein levels were significantly increased in the lymphocytes of Eμ-Tcl1-Tg:p53-/- mice relative to Eμ-Tcl1-Tg:p53+/+ mice. Exposure of leukemia cells isolated from Eμ-Tcl1-Tg:p53-/- mice to the EZH2 inhibitor 3-deazaneplanocin (DZNep) led to induction of apoptosis, suggesting EZH2 may play a role in promoting CLL cell survival and this may contribute to the aggressive phenotype of CLL with loss of p53. Our study reveals that the p53-miR30-EZH2 axis may play an important role in CLL pathogenesis, and EZH2 may potentially be a target for CLL treatment. Citation Format: Jinyun Liu, Marcia A. Ogasawara, Gang Chen, Helene Pelicano, Peng Huang. Characterization of TCL1-Tg:p53-/- mice that resemble human chronic lymphocytic leukemia with 17p-deletion: alterations in p53→Mir30→EZH2 axis. [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 3072. doi:10.1158/1538-7445.AM2013-3072