The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H

Abstract

Abstract Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) is a common molecular feature of different tumors. The oncogenic potential of IDH1R132 and its clinical prognostic value however, varies strongly between tumors of different tissues. Technologies to conduct functional investigations of isogentic controlled IDH1R132 in dependency of differentiation status offers a chance to understand underlying mechanisms of this heterogeneity or identify new tissue-dependent features of IDH1 mutation. Here we genetically engineered the first IDH1MUT model using human induced pluripotent stem cells (hiPSC) for inducible overexpression of IDH1R132H or its wildtype paralog. Confirming the known relevance of IDH1R132H, we identified a transcriptomic switch of hiPSC cells towards pro-angiogenetic program meanwhile suppression of p53 signaling upon oncogene induction. We chose neural differentiation of the cells and drug sensitivity testing to compare the influence of IDH1R132H on functional properties of the cells in tissue-specific context. Our results reveal the augmentation of drug resistance levels to clinical approved kinase inhibitors in induced neural stem cells, which was not observed in the pluripotent counterpart. Applying our technology in follow-up projects, such as comparing isogenic progenitor cells of different differentiation lineages, might help to understand a variety of tissue-related functions of IDH1 mutations. Moreover, given the fact that patient-derived human neuronal in vitro models with constitutive active IDH1R132H are challenging to establish, the presented work supports to overcome this limitation.