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 Assi, Paulynn Suyin Chin, Luke Ames, Roberto Avellino, Stephan Groeschel, Ruud Delwel, Peter Cockerill, Cameron S Osborne, Conny Bonifer

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
166 Downloads (Pure)

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
Number of pages18
JournalCell Reports
Volume28
Issue number12
DOIs
Publication statusPublished - 17 Sep 2019

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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