O03IDH1 MUTATIONS IN NEURAL STEM CELLS PROMOTE MIGRATION AND INVASION AND ACT SYNERGISTICALLY WITH P53 AND PTEN LOSS IN MURINE TUMOUR CELLS

INTRODUCTION: Over 70% of low- or high grade gliomas carry IDH1 gene mutations. The understanding of the role of IDH mutations in human glioma cells is limited by concomitant genetic and epigenetic modifications in glioma cell lines, making it difficult to precisely dissect the role of IDH in proliferation, migration and invasion. METHOD: Neural stem/progenitor cells (NSC) were isolated from the subventricular zone of mice carrying combinations of conditional gene mutations: IDH1R132H, p53lox/lox, Ptenlox/lox, or Rblox/lox. The IDH1 mouse model carries a cre-inducible human R132H allele. “Naive” neurospheres were recombined in vitro, and transferred to adherent conditions to form monolayers, for quantification of growth, invasion and migration. Further, we compared murine to human glioma initiating cells (hGIC) with wild-type or mutant IDH1. RESULTS: IDH mutations in mNSCs increased proliferation, migration and invasion but required inactivation of at least one additional tumour suppressor. In contrast, IDH mutant hGICs showed lower proliferation and wound healing rates than IDH wild type counterparts. CONCLUSION: Our study demonstrates an important role of mutant IDH in promoting growth, migration and invasion in murine primary NSC. The striking difference to human glioma cells may be explained by a different spectrum of mutations that have accrued in IDH mutant human tumours. We hypothesise that long-standing IDH mutations modify the epigenome differently from that in the short-term murine culture model. We are currently characterising the genome and methylome of murine IDH mutant cells during long-term in vitro culture and in our allografting paradigm to better characterise the role of IDH in tumourigenesis from NSC.