@article{7eaf2fc996a84a3a86d3895ebbf74a95,
title = "H3K27M/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 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 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 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.",
author = "Bernhard Lehnertz and Zhang, {Yu Wei} and Isabel Boivin and Nadine Mayotte and Elisa Tomellini and Jalila Chagraoui and Lavall{\'e}e, {Vincent Philippe} and Jos{\'e}e H{\'e}bert and Guy Sauvageau",
note = "Funding Information: This work was supported by the Government of Canada through Genome Canada and the Minist{\`e}re de l{\textquoteright}{\'E}conomie and de l{\textquoteright}Innovation et des Exportations du Qu{\'e}bec through G{\'e}nome Qu{\'e}bec, with supplementary funds from Amorchem and the Canadian Cancer Society Research Institute. G.S. and J.H. are recipients of research chairs from Industrielle-Alliance (Universit{\'e} de Montr{\'e}al) and the Canada Research Chair program, respectively. The Leukemia Cell Bank of Qu{\'e}bec is supported by grants from the Cancer Research Network of the Fonds de Recherche du Qu{\'e}bec–Sant{\'e} (FRQS). Sequencing read mapping and transcript quantification were performed on the supercomputer Briaree from the Universit{\'e} de Montr{\'e}al, managed by Calcul Qu{\'e}bec and Compute Canada. The operation of this supercomputer is funded by the Canada Foundation for Innovation, NanoQu{\'e}bec, R{\'e}seau de M{\'e}decine G{\'e}n{\'e}tique Appliqu{\'e}e, andFonds de Recherche du Qu{\'e}bec–Nature et Technologies. Y.W.Z is supported by a scholarship from FRQS. E.T. and V.-P.L. are supported by fellowships from the Cole Foundation Montreal. Publisher Copyright: {\textcopyright} 2017 by The American Society of Hematology.",
year = "2017",
month = nov,
day = "16",
doi = "10.1182/blood-2017-03-774653",
language = "English (US)",
volume = "130",
pages = "2204--2214",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",
}