STMC-21. ASTROCYTOMA MUTATIONS IDH1, p53 AND ATRX COOPERATE TO BLOCK DIFFERENTIATION OF NEURAL STEM CELLS VIA Sox2

The presence of a common IDH1 mutation in two divergent tumor lineages, astrocytoma and oligodendroglioma, suggests that it is a driver mutation that occurs early in the cascade of mutations in a progenitor-like cell. To test the hypothesis that mutant IDH1 is a driver of gliomagenesis, we used human embryonic stem cell derived neural stem cells (NSCs) to overexpress mutant IDH1 protein systematically in combination with p53 and ATRX knockdown, thereby modeling the mutations found in astrocytomas. Expression of mutant IDH1 resulted in robust production of 2-hydroxyglutarate. Mutant IDH1 alone paradoxically decreased proliferative capacity, increased apoptotic rates and blocked neuronal and astrocytic differentiation. The addition of p53 knockdown reversed all of these phenotypes. The third "oncogenic hit" of ATRX knockdown reverted the phenotype to a state characterized by normal proliferation and apoptotic rates, but maintained the block in differentiation. Analysis of the transcriptome and DNA methylome revealed that thousands of genes and methylation sites were also subject to a "switching" phenotype dependent on the oncogenic mutations present. Global comparisons of these transcriptomes and methylomes revealed NSCs with IDH1 mutations more closely resembled LGGs with IDH1 mutations, while control NSCs more closely resembled wild-type IDH1 LGGs. We found that Sox2, a master stem-cell transcription factor, was strikingly down-regulated in NSCs with oncogenic mutations that ...

Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Modrek, A., Golub, D., Khan, T., Zhang, G., Kader, M., Bowman, C., Prado, J., Bayin, N. S., Frenster, J., Lhakhang, T., Heguy, A., Dankert, J., Tsirigos, A., Snuderl, M., Neubert, T., Placantonakis, D. Tags: STEM CELLS Source Type: research