H3 K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations

Abstract

Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of <i>H3</i>^<i>K27M</i> 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 <i>H3</i>^<i>K27M</i> and <i>H3</i>^<i>K27I</i> 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 <i>RUNX1</i> gene. We demonstrate that <i>H3</i>^{<i>K27I/M</i>} 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.