Histone H3 K27M (H3K27M)

Histone H3 K27M is a recurrent somatic missense mutation involving the substitution of lysine 27 with methionine in histone H3 variants, most commonly H3.3 or H3.1. This "oncohistone" acts as a dominant-negative inhibitor of the Polycomb Repressive Complex 2 (PRC2) by sequestering the methyltransferase EZH2, leading to a global loss of the repressive H3K27 trimethylation (H3K27me3) mark and a reciprocal gain in H3K27 acetylation. These epigenetic alterations disrupt normal gene expression, promoting an undifferentiated, proliferative state in neural progenitor cells and driving the development of aggressive brain tumors. Clinically, H3K27M is the defining hallmark of Diffuse Midline Glioma (DMG), including Diffuse Intrinsic Pontine Glioma (DIPG), which are high-grade pediatric malignancies with a dismal prognosis. Therapeutic interventions currently under investigation include small molecules like ONC201, which targets mitochondrial proteases and dopamine receptors, epigenetic modifiers like HDAC inhibitors, and immunotherapies such as peptide vaccines and CAR-T cells targeting the mutation-specific neoepitope or associated surface antigens. Despite these advances, treating H3K27M-mutant tumors remains challenging due to the blood-brain barrier and the critical location of the tumors in the brainstem.

Other names

H3K27MHistone H3.3 K27MHistone H3.1 K27MLys27Met mutation in Histone H3Oncohistone H3K27MH3F3A K27MHIST1H3B K27M

The H3K27M mutation acts as a dominant-negative inhibitor of the Polycomb Repressive Complex 2 (PRC2) by sequestering its catalytic subunit, EZH2, through high-affinity binding of the mutant methionine residue. This sequestration leads to a global reduction in H3K27 trimethylation (H3K27me3) and a reciprocal increase in H3K27 acetylation (H3K27ac) at specific genomic loci. These changes result in the transcriptional activation of oncogenic pathways and the arrest of oligodendrocyte precursor cells in a proliferative, undifferentiated state. Therapeutic agents aim to reverse these epigenetic changes, induce apoptosis through mitochondrial stress (e.g., ONC201), or target the mutant protein as a neoantigen.