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Cell Rep. 2019 Jan 22;26(4):1059-1069.e6. doi: 10.1016/j.celrep.2018.12.098.

Chromatin-Based Classification of Genetically Heterogeneous AMLs into Two Distinct Subtypes with Diverse Stemness Phenotypes.

Author information

1
Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands.
2
Department of Hematology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
3
Dipartimento di Biochimica, Biofisica e Patologia generale, Università degli Studi della Campania "Luigi Vanvitelli," Vico L. De Crecchio 7, 80138 Napoli, Italy.
4
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, Spain.
5
Department of Hematology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
6
Department of Laboratory Medicine, Laboratory of Hematology, Radboud University, 6525 GA Nijmegen, the Netherlands.
7
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
8
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
9
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany.
10
Department of Molecular Biology, Faculty of Science, Radboud University, 6525 GA Nijmegen, the Netherlands. Electronic address: j.martens@ncmls.ru.nl.

Abstract

Global investigation of histone marks in acute myeloid leukemia (AML) remains limited. Analyses of 38 AML samples through integrated transcriptional and chromatin mark analysis exposes 2 major subtypes. One subtype is dominated by patients with NPM1 mutations or MLL-fusion genes, shows activation of the regulatory pathways involving HOX-family genes as targets, and displays high self-renewal capacity and stemness. The second subtype is enriched for RUNX1 or spliceosome mutations, suggesting potential interplay between the 2 aberrations, and mainly depends on IRF family regulators. Cellular consequences in prognosis predict a relatively worse outcome for the first subtype. Our integrated profiling establishes a rich resource to probe AML subtypes on the basis of expression and chromatin data.

KEYWORDS:

AML; DNA accessibility; acute myeloid leukemia; chromatin states; epigenome; histone marks; stemness; transcriptome

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