Histone H3.3 K27M mutant protein (H3K27M)

The Histone H3.3 K27M (H3K27M) mutant protein is a recurrent somatic mutation that serves as a primary driver in diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG) (Source: Wu et al., Nature Genetics, 2012). This mutation involves a substitution of lysine 27 with methionine, which acts as a dominant-negative inhibitor of the Polycomb Repressive Complex 2 (PRC2) (Source: Lewis et al., Science, 2013). This inhibition leads to a global reduction in H3K27 trimethylation (H3K27me3), resulting in aberrant gene expression and a failure of cellular differentiation. As a tumor-specific neoantigen, the H3K27M peptide is an ideal target for immunotherapy because it is not expressed in healthy tissues. Therapeutic interventions include peptide vaccines that aim to elicit B cell-mediated antibody production and T cell responses against the mutant epitope (Source: Mueller et al., Journal of Clinical Oncology, 2019). Additionally, researchers are developing "TCR-like" monoclonal antibodies that can recognize the H3K27M peptide when presented by specific HLA molecules on the tumor cell surface (Source: Chheda et al., Nature, 2018). These antibody-based strategies are designed to recruit the immune system to selectively destroy glioma cells within the central nervous system. Clinical trials are currently evaluating the safety and efficacy of these targeted approaches in pediatric and adult patients with H3K27M-mutant tumors.

Other names

H3F3A K27MHistone H3.3 Lys27MetOncohistone H3K27MH3.3K27MH3K27M neoantigen

Induction of a targeted immune response against tumor cells expressing the H3K27M neoantigen through peptide vaccination or the use of antibodies that recognize the mutant epitope presented on the cell surface.