Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3^K27M mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di- and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3^K27M and H3^K27I mutations in patients with AML. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they are associated with common aberrations in the RUNX1 gene. We demonstrate that H3^K27I/M mutations are strong disease accelerators in a RUNX1-RUNX1T1 AML mouse model, suggesting that H3K27me2/3 has an important and selective leukemia-suppressive activity in this genetic context.

影响组蛋白H3基因中关键赖氨酸残基的新态错义突变显着促成多种实体癌。尽管小儿胶质母细胞瘤中H3 ^K27M突变的患病率很高，并且它们对整体组蛋白H3赖氨酸27二甲基和三甲基化（H3K27me2 / 3）具有公认的影响，但尚未在急性髓细胞性白血病（AML）中研究这些突变的相关性。在这里，我们报告首次发现AML患者中的H3 ^K27M和H3 ^K27I突变。我们发现这些病变是这些患者中H3K27me2 / 3减少的主要决定因素，并且它们与RUNX1基因的常见异常有关。我们证明H3在RUNX1-RUNX1T1 AML小鼠模型中， ^{K27I / M}突变是强大的疾病促进剂，这表明H3K27me2 / 3在这种遗传背景下具有重要的选择性白血病抑制活性。