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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin* / genetics
  • Chromatin* / metabolism
  • Chromatin* / pathology
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Core Binding Factor Alpha 2 Subunit* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / classification
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mutation*
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Oncogene Proteins, Fusion* / genetics
  • Oncogene Proteins, Fusion* / metabolism

Substances

  • Chromatin
  • Core Binding Factor Alpha 2 Subunit
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • RUNX1 protein, human
  • nucleophosmin