Abstract LB-106: A novel TCL1-Tg:p53−/−mouse model of human CLL

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. CLL patients with loss of p53 due to chromosome 17p deletion often exhibit more malignant disease phenotype, are refractory to standard treatment, and have poor clinical outcomes. Although there are several mouse models that resemble the chronic disease processes of CLL, no animal model has been reported that mimic the aggressive disease phenotype of CLL with loss of p53. To facilitate the investigation of the biology of aggressive CLL with loss of p53 and the underlying mechanisms, we generated a mouse model with Eu-TCL1-Tg:p53−/− genotype by crossing the Eu-TCL1-Tg mice with p53 knockout mice. The Eu-TCL1-Tg:p53−/- mice developed CLL disease at 3-4 months, significantly earlier than the parental Eu-TCL1-Tg mice that developed CLL disease at 8-12 months. Flow cytometry analysis showed that the IgM+/CD5+ cell population appeared in the peritoneal cavity, bone marrow, and the spleens of Eu-TCL1-Tg:p53−/- mice significantly earlier than that of the parental Eu-TCL1-Tg mice. Massive infiltration and accumulation of leukemia cells were found in the spleen, liver, and peritoneal cavity. In vitro study showed that the leukemia cells isolated from the Eu-TCL1-Tg:p53−/- mice were more resistant to fludarabine treatment than the leukemia cells isolated from spleens of TCL1-Tg mice. Interestingly, TUNEL assay revealed that there was higher apoptotic cell death found in the TCL1-Tg spleen tissue compared to the spleens of the Eu-TCL1-Tg:p53−/- mice, suggesting that the loss of p53 compromises the apoptotic process in vivo, and this might in part explain the drug resistant phenotype of CLL cells with 17p deletion. Further molecular analysis showed that the expression of MCL-1, a key survival molecule for CLL, was significantly increased at the mRNA and protein levels in the leukemia cells isolated from Eu-TCL1-Tg:p53−/- mice, which seemed to be associated with the abnormal expression of certain microRNAs including miR15a and miR-16. Overall, the Eu-TCL1-Tg:p53−/- mice display a disease phenotypes that resemble human CLL with 17p deletion, and represent a useful animal model for mechanistic study as well as evaluation of in vivo therapeutic efficacy of anti-CLL agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-106. doi:1538-7445.AM2012-LB-106