Inactivation of Pten cooperating with p53 loss induces malignant gliomas

320 Malignant gliomas, due to their rapid growth and tendency to spread throughout the brain and spinal cord, remains one of the greatest clinical challenges and is considered to be among the deadliest human cancers. Like other malignancies, human gliomas have been associated with many molecular genetic abnormalities. Among them, alterations in the p53 and PI3K pathways have been found in virtually all high-grade gliomas. In this study, we have generated a malignant glioma mouse model with high penetrance that harbors both a conditional allele of p53 and a conditional allele of the Pten tumor suppressor gene that negatively regulates PI3K signaling. These tumors are highly aggressive, bearing striking resemblance clinically and pathologically to their human counterparts; namely uncontrolled cellular proliferation,diffuse infiltration, propensity for necrosis. We find that the earliest evidence of tumor formation localizes to different regions of the brain that contain progenitor populations. Additionally, the presence of extensive inter- and intra-tumoral histological heterogeneity suggests these tumors may originate from different progenitor linages. Furthermore, our in vivo and in vitro results indicate while Pten deletion promotes neural stem/progenitor cell early expansion, subsequent inactivation of p53 is required to maintain their progenitor activity and shift the homeostatic balance towards proliferation of this niche. Consistent with these findings, we find p53 is directed mutated in 40% our thirty-five analyzed human primary gliobastoma samples. Strikingly, Pten is concurrently mutated and/or deleted in 70% of these samples Together, this faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.