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

Cell Rep. 2015 Aug 4;12(5):821-36. doi: 10.1016/j.celrep.2015.06.069. Epub 2015 Jul 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • MAP Kinase Signaling System*
  • Male
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation*
  • Protein Structure, Tertiary
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human
  • Transcription Factor AP-1
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Mitogen-Activated Protein Kinase Kinases

Associated data

  • GEO/GSE64874