Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence

Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24+ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors

Gene Therapy Approaches Using Reproducible and Fully Penetrant Lentivirus-Mediated Endogenous Glioma Models

Animal models have proven invaluable for progress toward greater understanding of the etiology, pathogenesis, and genetics of a wide range of human diseases. The development of relevant brain tumor animal models is a critical resource for building our understanding of cancers that arise within the brain and for the development of novel therapies. The central role of these models is particularly apparent for gliomas, which are common and devastating primary brain tumors. Effective models accurately demonstrate pathological features and behavior that are analogous to the human disease. Models aim to develop tumors with high penetrance and low latency, features that are ideal for preclinical therapeutic development. Lentiviral vector-induced models fulfill these requirements while giving investigators excellent control over the genetic profile of resulting tumors. This flexibility is especially relevant in the context of recent advances in the understanding of the genetic lesions found in human grade IV glioma, glioblastoma multiforme (GBM). Further, these endogenous tumor models would be ideal for the testing of novel gene therapy strategies which could potentially be implemented in Phase 1 clinical trials for these devastating human brain cancers.Fil: Lynes, John. University Of Michigan Medical School; Estados UnidosFil: Koschmann, Carl. University Of Michigan Medical School; Estados UnidosFil: Wibowo, Mia. University Of Michigan Medical School; Estados UnidosFil: Saxena, Vandana. University Of Michigan Medical School; Estados UnidosFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Moreno Ayala, Mariela Alejandra. University Of Michigan Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Castro, Maria Graciela. University Of Michigan Medical School; Estados UnidosFil: Lowenstein, Pedro R.. University Of Michigan Medical School; Estados Unido