A new report published in Science from the lab of Viviane Tabar, MD, at Memorial Sloan-Kettering, describes the ability to model a rare type of pediatric brain tumor for the first time using human embryonic stem cell-based techniques. Diffuse intrinsic pontine gliomas (DIPGs) are tumors of the brainstem that are primarily found in children. Most DIPGs have mutations in a gene encoding histone H3.3. Histones are multi-unit proteins that package DNA in the nucleus; chemical changes to the histone proteins (also called “epigenetic modifications”) can alter the expression of many key genes. Dr. Tabar’s group examined one specific mutation in histone H3.3, conversion of lysine 27 to methionine. Histone H3.3’s lysine 27, normally a target of epigenetic modifications, is mutated in 70% of DIPGs. Two other common mutations in DIPGs are in a growth factor receptor, PDGFRA, and a tumor suppressor, p53. Dr. Tabar’s research team used human embryonic stem cells to produce neural progenitor cells (NPCs), then expressed the mutant histone H3.3 along with PDFGRA, and inactivated p53. This combination of changes in the NPCs recapitulated molecular changes that are observed in cancer cells derived from DIPG patients. These modifications acted synergistically, producing cells that divided rapidly, were resistant to cell death and differentiation, and appeared less mature – more like stem cells – compared to normal NPCs. Screening of the new, transformed cells identified a drug that can suppress their overgrowth both in vitro and in animal models, suggesting the possibility of a therapeutic approach for this fatal cancer. Use of the hES system as a platform to model cancer is a promising advance in both stem cells and oncology. It allowed insight into the mechanisms of tumor formation and highlighted the critical developmental window during which these specific tumors are formed. Preliminary data also suggest that the drug identified in the screen has an equally effective impact on patient tumors. This research was supported by a NYSTEM research award, C026418, to Dr. Tabar.
Funato K, Major T, Lewis PW, Allis CD, Tabar V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science. 2014, Dec 19: 346(6216):1529-33.