Histone H3-K27M mutant neoantigen (H3-K27M)

The Histone H3-K27M mutant neoantigen is a tumor-specific protein fragment resulting from a point mutation in the H3F3A or HIST1H3B genes, where lysine 27 is replaced by methionine. This mutation is a hallmark of diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG), and acts as a powerful epigenetic driver by inhibiting the Polycomb Repressive Complex 2 (PRC2), leading to a global loss of H3K27 trimethylation and aberrant gene expression (Lewis et al., 2013; Filbin et al., 2018). Because this mutation is highly specific to malignant cells and absent in healthy tissue, it serves as an ideal neoantigen for precision immunotherapy. Current therapeutic strategies include peptide vaccines and TCR-engineered T-cells designed to recognize the K27M epitope presented on the cell surface by specific HLA alleles (Mueller et al., 2019). Additionally, small molecule inhibitors are being explored to exploit the downstream epigenetic and metabolic dependencies created by this mutation in pediatric and adult high-grade gliomas (Chi et al., 2022).

Other names

H3K27MHistone H3 lysine 27-to-methionine mutationH3.3K27MH3.1K27MDiffuse midline glioma H3 K27-mutant neoantigen

The H3-K27M mutant neoantigen is targeted primarily through immunotherapy, where synthetic peptides or engineered T-cells (TCR-T) recognize the specific K27M mutation presented by HLA molecules (typically HLA-A*02:01) to induce a cytotoxic immune response against tumor cells (Chheda et al., 2018; Mueller et al., 2019). Small molecules like ONC201 act by antagonizing dopamine receptors D2/D3 and activating mitochondrial protease ClpP, which indirectly targets the metabolic and epigenetic vulnerabilities created by the H3-K27M mutation (Chi et al., 2022).