Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature

Research output: Contribution to journalArticlepeer-review

Authors

External organisations

  • Section of Experimental Haematology
  • Leeds Institute for Molecular Medicine
  • University of Leeds
  • Warwick Systems Biology Centre
  • University of Warwick
  • West Midlands Regional Genetics Laboratory
  • Birmingham Women's NHS Foundation Trust
  • Haematological Malignancy Diagnostic Service
  • St. James's University Hospital
  • School of Molecular and Cellular Biology
  • Faculty of Biological Sciences

Abstract

Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.

Bibliographic note

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Details

Original languageEnglish
Pages (from-to)821-836
Number of pages16
JournalCell Reports
Volume12
Issue number5
Early online date23 Jul 2015
Publication statusPublished - 4 Aug 2015

Keywords

  • acute myeloid leukaemia