Histone H3.3 K27M (H3.3K27M)

Histone H3.3 K27M is a specific somatic missense mutation in the H3F3A gene, resulting in the substitution of lysine with methionine at position 27 of the histone H3.3 protein [1, 8]. This 'oncohistone' is the hallmark of diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), which are highly aggressive pediatric brain tumors [5, 13]. The mutation acts as a dominant-negative inhibitor of the Polycomb Repressive Complex 2 (PRC2) by sequestering its catalytic subunit, EZH2, which leads to a global loss of the repressive H3K27me3 mark and a redistribution of H3K27 acetylation [1, 9, 21]. This epigenetic reprogramming drives oncogenesis by de-repressing genes involved in cell proliferation and blocking neural differentiation [6, 19]. Therapeutic strategies include indirect targeting via imipridones like ONC201, which exploits mitochondrial stress pathways, and direct targeting through neoantigen-based vaccines and TCR-T cell therapies [12, 14, 22]. Despite these advances, the mutation remains associated with a dismal prognosis and significant therapeutic challenges, including the blood-brain barrier and tumor resistance [13, 14].

Other names

H3F3A K27MH3.3 Lys27MetOncohistone H3.3 K27MH3-3A K27MHistone H3.3 K27M mutant

Drugs targeting H3.3 K27M-mutant tumors act through various mechanisms: ONC201 and ONC206 function as dopamine receptor D2/D3 antagonists and ClpP agonists to induce mitochondrial stress and apoptosis [12, 22]; HDAC inhibitors like Panobinostat and Vorinostat reverse aberrant histone acetylation patterns [2, 10]; and peptide vaccines or TCR-T cells elicit a specific immune response against the K27M neoantigen [14, 15]. The mutation itself inhibits PRC2 (EZH2) activity, leading to global H3K27me3 loss [1, 9].