LOSS OF PTEN AND TRP53 IN OLIGODENDROCYTE PROGENITORS LEADS TO GLIOMA FORMATION

Abstract Tumor suppressors PTEN and TP53 are the most commonly mutated anti-oncogenes in human gliomas after TERT mutation. 38% and 17% of total 4023 samples of gliomas in TCGA show TP53 and PTEN mutations respectively. TP53 signaling pathway plays an important role in the suppression of tumor progression PTEN negatively regulates PI3 triphosphate levels and suppresses AKT/PKB pathways. In-frame and missense mutations in PTEN constitutively activates the proliferative pathway and give a survival advantage. Mice with conditional mutation of PTEN and TP53 in neural stem cells directed by hGFAP-Cre develop high-grade gliomas. Our recent study indicates that primitive oligodendrocyte-progenitor intermediates (Pri-OPC) are abundant and hyperproliferative cells and can be progressively reprogrammed towards a stem-like state susceptible to malignant transformation. We hypothesize that mutations in PTEN and TP53 in pri-OPC lineage cells can lead to glioma formation. OPCs distribute across the whole adult brain and exhibit a much higher number than NSCs that are restricted to very small niche areas. Olig1 and Olig2 mark pri-OPC and oligodendrocyte lineage cells. In this study, we inactivated the PTEN/TP53 gene in mouse pri-OPCs using Olig1-Cre or Olig2tva-Cre. The incidence of glioma formation was 100%. Both the tumor formed in these models display multifocal, high-grade, diffuse and infiltrating gliomas. Though tumors are derived from similar cell sources, they vary in the expression and extent of oncogenic pathways. Our transcriptomics profiling at different stages of tumorigenesis reveals that progressive activation of oncogenic signaling pathways establishes a tumorigenic state to promote malignant transformation, suggesting a dynamic process of tumorigenesis caused by the cooperative action of the PTEN and TP53 loss in the pri-OPC lineage.