Abstract 521: Glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling

Abstract

Abstract Point mutations in isocitrate dehydrogenase enzymes (IDH1 and IDH2) have been identified in 70-90% of lower-grade gliomas (LGGs; WHO grade II and III) as foundational genomic alterations. Glioma-associated IDH mutations occur in active site arginine residues and confer a neomorphic activity resulting in overproduction of the oncometabolite R(-)-2-hydroxyglutarate (2HG). The affects of 2HG on cellular physiology are widespread and include global shifts in epigenomic profiles. LGGs have also been repeatedly linked with dysregulated platelet-derived growth factor (PDGF) signaling. We have recently demonstrated that miR-34a is downregulated in gliomas in response to dysregulated PDGF signaling and that miR-34a directly targets the PDGF receptor (PDGFRA) in high-grade gliomas. Analyzing a panel of diffuse gliomas, we find that miR-34a is specifically downregulated in LGG in response to IDH mutation. Similarly, in multiple isogenic cell line systems, IDH mutation induces repression of miR-34a. Also in these contexts, IDH mutation induces neurosphere formation and the expression of stem cell-associated genes. miR-34a has been reported to target pluripotency factors such as LIN28, OCT4 and NANOG. Accordingly, we find that murine neuroglial progenitor cells expressing IDH mutant isoform express higher levels of these factors than isogenic controls. The stem cell-like phenotype of IDH mutant-expressing cells is morphologically reversed by restoring miR-34a expression in the cells. Despite findings that IDH mutation correlates with hypermethylation at the MIR34a locus in LGG tumors, we have not been able to demonstrate the functional relevance of this. Instead, we find that IDH mutation is associated with enhanced PDGF signaling, and we demonstrate that inhibition or stimulation of PDGF signaling in IDH mutant cells increases or decreases miR-34a expression, respectively. Our studies support a model in which glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling. Citation Format: Joachim Silber, Girish Harinath, Prasanna Tamarapu Parthasarathy, Armida W.M. Fabius, Sevin Turcan, Timothy A. Chan, Jason T. Huse. Glioma-associated IDH mutation induces miR-34a repression and stem cell-like physiology through enhanced PDGF signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 521. doi:10.1158/1538-7445.AM2014-521