Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation
Menée à l'aide de cellules souches embryonnaires, cette étude met en évidence le rôle joué par une mutation de l'histone H3.3, en coopération avec une perte du gène p53 et une activation de la signalisation PDGRA, dans la croissance tumorale d'un gliome infiltrant du tronc cérébral
Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem (ES) cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human ES cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein Menin as an inhibitor of tumor cell growth in vitro and in mice.