The Role of Tumor Suppressor Genes P53 and NF1 in Neural Stem Cells and Brain Tumor Development.

Abstract

Glioblastoma multiforme (GBM) is the most frequent and infiltrative neoplasm among human primary brain tumors. Highly resistant to conventional radiation and chemotherapy, GBM is one of the most deadly human cancers with a median survival of 12 months that has remained unimproved over the past two decades. Recent studies have identified that tumor suppressor genes TP53 and Neurofibromatosis Type 1 (NF1) are two of the most frequently mutated genes in human GBM. However, how deficiency in these tumor suppressor genes transforms normal brain cells into malignancy is not yet understood. Further, the cell of origin for glioma remains largely unknown.

This thesis work utilizes transgenic mouse models to understand the role of p53 and Nf1 in normal neural stem/progenitor cell function and how inactivation of these genes transforms neural stem/progenitor cells and leads to neurological diseases. In the p53 model, p53 deficiency is sufficient for glioma formation by allowing the accumulation of cooperative oncogenic alterations. In addition, the accumulation of mutant p53 protein can be used to trace the early lesions in the brain, which occur first in neural stem cells in the subventricular zone (SVZ) stem cell niche. Subsequent expansion of mutant p53-expressing transit-amplifying progenitor-like cells in the SVZ-associated areas initiates glioma formation. This study establishes a critical role of p53 deficiency in gliomagenesis, and provides insight into the cell-of-origin for glioma. In the Nf1 mouse model, Nf1 deficiency alone is insufficient for glioma formation and only appears to confer a transient growth advantage to neural progenitor cells during development, which does not persist into adulthood. The critical role of Nf1 is to regulate neuron/glia fate determination of neural progenitor cells. Bi-allelic Nf1 inactivation causes ectopic Olig2 expression specifically in transit-amplifying progenitors, causing increased gliogenesis at the expense of neurogenesis. In addition, Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect recently linked to NF1-associated learning disabilities. These NF1-associated developmental defects can be reversed by treatment with a MEK inhibitor during neonatal stages. Together, this study not only provides insights into fate-determination of SVZ progenitor cells, but also identifies a potential therapeutic window for treating NF1-associated brain abnormalities.