Histone H3.3-K27M neoantigen (H3.3K27M)

Histone H3.3-K27M is a tumor-specific neoantigen resulting from a recurrent point mutation (lysine 27 to methionine) in the H3F3A gene, which is a hallmark of pediatric diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma (DIPG) (Lewis et al., Science, 2013). This mutation acts as an oncohistone by binding and inhibiting the Polycomb Repressive Complex 2 (PRC2), leading to a global loss of H3K27 trimethylation and subsequent epigenetic reprogramming that drives tumorigenesis (UniProt P84243). Because the K27M substitution creates a unique amino acid sequence not found in healthy tissue, it serves as a highly specific neoantigen for immunotherapy. Current therapeutic strategies focus on peptide-based vaccines and T-cell receptor (TCR) engineered T-cell therapies designed to recognize the K27M epitope presented by HLA-A*02:01 (Chheda et al., Nature Medicine, 2018). These approaches aim to elicit a targeted cytotoxic T-lymphocyte response against glioma cells while minimizing off-target toxicity in the central nervous system (Mueller et al., Journal of Clinical Oncology, 2020). Additionally, small molecules like ONC201 are utilized in patients harboring this mutation to exploit specific metabolic and stress-response vulnerabilities associated with the H3K27M-altered epigenetic landscape.

Other names

H3F3A K27MHistone H3.3 lysine 27-to-methionineH3.3 K27M mutant proteinOncohistone H3.3K27MH3.3K27M epitope

Induction of tumor-specific immune responses via T-cell receptor recognition of the mutant K27M peptide fragment presented on HLA-A*02:01 molecules, or indirect metabolic/epigenetic stress induction.