Subtype-specific regulatory network rewiring in acute myeloid leukemia

Salam A Assi, Maria Rosaria Imperato, Daniel J L Coleman, Anna Pickin, Sandeep Potluri, Anetta Ptasinska, Paulynn Suyin Chin, Helen Blair, Pierre Cauchy, Sally R James, Joaquin Zacarias-Cabeza, L Niall Gilding, Andrew Beggs, Sam Clokie, Justin C Loke, Phil Jenkin, Ash Uddin, Ruud Delwel, Stephen J Richards, Manoj RaghavanMichael J Griffiths, Olaf Heidenreich, Peter N Cockerill, Constanze Bonifer

Research output: Contribution to journalArticlepeer-review

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

Original languageEnglish
Pages (from-to)151-162
Number of pages12
JournalNature Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Gene Expression Regulation, Leukemic/genetics
  • Gene Regulatory Networks/genetics
  • Humans
  • Leukemia, Myeloid, Acute/genetics
  • Male
  • Middle Aged
  • Nucleophosmin
  • Signal Transduction/genetics
  • Transcription Factors/genetics
  • Young Adult

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