Therapeutical reprogramming of DIPG cells
Dr. Nadia Dahmane – Joan & Sanford I. Weill Medical College of Cornell University, New York, NY
Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric glioma arising in the developing pons, has no cure and an overall survival of less than one year making it the most lethal brain tumor in children. Novel therapeutic approaches are therefore desperately needed. Defects in the epigenetic landscape such as global decreased levels of H3K27trimethylation (H3K27me3) may drive DIPG tumorigenesis. How DIPGs arise and grow in the developing pons is not known. We have identified a novel transcription factor, RP58, as a regulator of brain development. Our preliminary data show that RP58 is required for pons development. In addition, expression of RP58 in glioma cells affects their epigenetic landscape by increasing H3K27me3 levels. We hypothesize that RP58 is required to maintain cell differentiation in the developing pons and that its loss in this context may lead to epigenetic changes that will cause increased tumorigenesis. Our goals are thus to: 1) decipher the critical role of RP58 in cell differentiation during in pons development using Rp58 loss-of-function mouse models; 2) determine if and how RP58 contributes to DIPG development in particular by testing whether reintroduction of RP58 in DIPG cells may be a therapeutic strategy in vitro using human patient-derived DIPG cells, and in vivo using orthotopic and genetic mouse models of DIPG.
