Histone H3 lysine 27-to-methionine mutant (H3K27M)

Histone H3 lysine 27-to-methionine (H3K27M) is a recurrent somatic gain-of-function mutation primarily associated with pediatric diffuse midline gliomas (DMGs) and diffuse intrinsic pontine gliomas (DIPGs). This mutation occurs most frequently in the H3.3 (H3F3A) or H3.1 (HIST1H3B) histone variants and involves the substitution of a critical lysine residue with methionine at position 27 on the N-terminal tail. The mutant protein functions as a potent inhibitor of the Polycomb Repressive Complex 2 (PRC2) by sequestering the EZH2 methyltransferase, which results in a global reduction of the repressive H3K27me3 epigenetic mark and subsequent transcriptomic dysregulation that maintains cells in a stem-like, proliferative state. Therapeutically, the H3K27M mutation provides multiple avenues for intervention, including the use of epigenetic modulators like histone deacetylase (HDAC) inhibitors and small molecules such as dordaviprone (ONC201) that exploit specific mitochondrial vulnerabilities in mutant cells. Additionally, because the mutation creates a unique peptide sequence not found in healthy tissue, it serves as a highly specific neoantigen for immunotherapies, including peptide vaccines and TCR-T cell therapies currently in clinical trials. The presence of the H3K27M mutation is a definitive diagnostic and prognostic marker, as it identifies aggressive WHO grade 4 tumors that are historically resistant to conventional radiation and chemotherapy.

Other names

H3.3K27MH3.1K27MH3K27M-mutated histone H3Histone H3 K27MK27M-mutated histone-3 sequenceH3F3A K27MHIST1H3B K27M

The H3K27M mutant histone acts as a dominant-negative inhibitor of the Polycomb Repressive Complex 2 (PRC2) by binding and sequestering its catalytic subunit, EZH2, leading to a global loss of the repressive H3K27 trimethylation (H3K27me3) mark and a localized gain of the activating H3K27 acetylation (H3K27ac) mark. Therapeutic strategies involve either inhibiting epigenetic enzymes to restore balance (e.g., HDAC or JMJD3 inhibition), over-activating mitochondrial ClpP to induce cancer cell death (e.g., imipridones like ONC201), or targeting the mutant sequence as a tumor-specific neoantigen to stimulate a T-cell-mediated immune response.