Abstract IA14: Targeting the PTEN/PI3K pathway: From mouse model to human cancer

Abstract

Abstract Disease relapse represents a significant problem in treating T cell acute lymphoblastic leukemia (T-ALL), particularly in the context of PTEN alterations. It is hypothesized that leukemia-initiating cells (LICs) are responsible for both T-ALL development and treatment relapse. Here, we use the Pten null T-ALL model with functionally defined blast and LIC-enriched populations to test whether T-ALL LICs are responsible for therapeutic resistance. In this model, disease is initiated by the conditional deletion of Pten in the fetal liver hematopoietic stem cells and animals develop T-ALL with 100% penetrance in the absence of activating Notch1 mutations. Besides Pten deletion, at least two subsequent key events associated with human leukemogenesis have been identified, namely β-catenin activation and a T cell receptor α-c-Myc (Tcrα/δ-c-Myc) translocation, which lead to the transformation of T progenitor cells to self-renewable LICs enriched in the CD3+c-kitmidLin- subpopulation. In contrast to LICs in acute and chronic myelogenous leukemia, in vivo labeling revealed that T-ALL LICs are actively cycling. Furthermore, we demonstrate that T-ALL LICs are biologically distinct and respond differently to Rapamycin in comparison to their differentiated blast cell progeny. Importantly, we found that co-targeting deregulated phosphoinositide 3-kinase (PI3K) and Myc pathways, two common alterations found in human T-ALL that are associated with LIC formation in vivo, provides a potent therapeutic approach to eliminate T-ALL LICs. Our study suggests that LICs are addicted to molecular events critical for their formation and can be effectively eliminated by targeting these alterations, and that T-ALL may be stratified and treated according to such molecular defects. Citation Format: Hong Wu. Targeting the PTEN/PI3K pathway: From mouse model to human cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA14.