RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

Cell Rep. 2019 Sep 17;28(12):3022-3031.e7. doi: 10.1016/j.celrep.2019.08.040.


Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.

Keywords: AP-1 signaling in acute myeloid leukemia; Promoter-Capture Hi-C; RUNX1-ETO; acute myeloid leukemia; chromatin programming; epigenetic regulation; integrated analysis of high-throughput data; promoter-enhancer interactions; transcription factors; transcriptional networks.

MeSH terms

  • CCAAT-Enhancer-Binding Proteins* / genetics
  • CCAAT-Enhancer-Binding Proteins* / metabolism
  • Chromosomes, Human, Pair 21 / genetics
  • Chromosomes, Human, Pair 21 / metabolism
  • Chromosomes, Human, Pair 8 / genetics
  • Chromosomes, Human, Pair 8 / metabolism
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Core Binding Factor Alpha 2 Subunit* / metabolism
  • Enhancer Elements, Genetic*
  • Gene Deletion
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Oncogene Proteins, Fusion* / genetics
  • Oncogene Proteins, Fusion* / metabolism
  • Promoter Regions, Genetic*
  • RUNX1 Translocation Partner 1 Protein* / genetics
  • RUNX1 Translocation Partner 1 Protein* / metabolism
  • Transcription Factor AP-1* / genetics
  • Transcription Factor AP-1* / metabolism
  • Translocation, Genetic*


  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Transcription Factor AP-1