Advertisement

H3K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations.

Bernhard Lehnertz, Yu Wei Zhang, Isabel Boivin, Nadine Mayotte, Elisa Tomellini, Jalila Chagraoui, Vincent-Philippe Lavallée, Josée Hébert and Guy Sauvageau

Key points

  • First characterization of neomorphic H3K27 mutations in AML.

  • H3K27 mutations associate and collaborate with RUNX1 mutations and translocations.

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 H3K27M 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 H3K27M and H3K27I mutations in AML patients. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they associate with common aberrations in the RUNX1 gene. We demonstrate that H3K27I/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.

  • Submitted March 22, 2017.
  • Accepted August 23, 2017.