Histone H3-K27M mutant protein (H3-K27M) (H3-K27M)

Histone H3-K27M mutant protein is a pathognomonic "oncohistone" resulting from a point mutation in the H3F3A (H3.3) or HIST1H3B/C (H3.1) genes, where lysine 27 is substituted with methionine [1, 2]. This mutation is the defining molecular feature of Diffuse Midline Glioma (DMG), H3 K27-altered, a highly aggressive pediatric brain tumor [3]. Mechanistically, the K27M mutant histone 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 H3K27 trimethylation (H3K27me3) mark [2, 4]. This epigenetic remodeling causes the aberrant re-expression of genes that promote tumorigenesis and prevent neural differentiation [4]. While the mutant protein itself is difficult to target directly, therapeutic approaches focus on downstream effects or metabolic vulnerabilities, with ONC201 (an imipridone) showing significant clinical activity by targeting mitochondrial ClpP and dopamine receptors D2/D3 in H3-K27M-mutant cells [5, 6]. Additionally, epigenetic modifiers such as HDAC inhibitors are being explored to reverse the transcriptional dysregulation caused by the mutation [4]. Sources: [1] Wu G, et al. (2012) Nature Genetics; [2] Lewis PW, et al. (2013) Science; [3] Louis DN, et al. (2021) Neuro-Oncology; [4] Bender S, et al. (2013) Cancer Cell; [5] Chi AS, et al. (2022) JCO; [6] Ishida CT, et al. (2018) Oncotarget.

Other names

H3K27MH3.3 K27MH3.1 K27MLysine 27-to-methionine mutation in histone H3

Inhibition of Polycomb Repressive Complex 2 (PRC2) activity through EZH2 sequestration; activation of mitochondrial ClpP and antagonism of dopamine receptors D2/D3 (via ONC201); inhibition of histone deacetylases (HDAC).