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

Anetta Ptasinska, Anna Pickin, Salam A. Assi, Paulynn Suyin Chin, Luke Ames, Roberto Avellino, Stephan Gröschel, Ruud Delwel, Peter N. Cockerill, Cameron S. Osborne, Constanze Bonifer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3022-3031.e7
JournalCell Reports
Volume28
Issue number12
DOIs
Publication statusPublished - 17 Sept 2019

Keywords

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

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