Epigenetic Basis for the Oncogenic Potential of IDH Mutations

Although many complex diseases including cancer manifest aberrant cellular metabolism and chromatin structure, the molecular connection between two processes remains poorly understood. The metabolite, αketoglurate (αKG), is a critical co-factor for a number of chromatin modifying enzymes. Its structural analogue, 2-hydroxyglutarate (2HG), was recently identified as the product of cancer-associated mutations in isocitrate dehydrogenases (IDH). To determine whether metabolic perturbation can disrupt chromatin remodeling and transcription, I investigated the epigenetic consequences of 2HG-producing IDH mutations. In this thesis, 2HG was demonstrated to be a competitive inhibitor for αKG-dependent chromatin modifiers including TET family DNA hydroxylases and jumonji-C histone demethylases. Expression of mutant IDH in cell lines led to global increases in histone and DNA methylation. In patient tumor samples, IDH mutations were tightly associated with DNA and histone hypermethylation and were mutually exclusive with loss of function mutations in TET2. Importantly, IDH mutation impaired cell differentiation which could be phenocopied by exogenous 2HG or depletion of 2HG-inhibitable TET2 or histone demethylase. Moreover, mutant IDH was sufficient for in vitro transformation and in vivo tumorigenesis and its malignant potential could be attributed to epigenetic gene silencing through DNA hypermethylation. Collectively, the data presented in this thesis provide insight into the tumorigenic mechanism by IDH mutations and suggest that both normal and neomorphic metabolite levels contribute to chromatin structure and transcriptional regulation. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Craig B. Thompson Second Advisor Roger A. Greenberg