Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) 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 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 embryonic stem 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.

Modeling brain cancer from stem to stern

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive brain tumors primarily affecting children. Because the tumors arise in the brainstem, which controls many vital functions, they cannot be surgically excised and are often fatal. To study the pathogenesis of DIPGs—in particular, the role of a histone H3.3 mutation that occurs in 70% of cases—Funato et al. developed a new tumor model (see the Perspective by Becher and Wechsler-Reya). They first directed the differentiation of embryonic stem cells into neural progenitor cells. They then introduced a specific combination of genes, including the mutant histone gene, and found that this caused the progenitor cells to acquire features characteristic of cancer cells. During this oncogenic transformation, the cells reverted to a more primitive differentiation state and displayed altered histone marks at several key regulatory genes.

Science, this issue p. 1529; see also p. 1458