Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells

Monica Nafria, Peter Keane, Elizabeth S Ng, Edouard G Stanley, Andrew G Elefanty, Constanze Bonifer

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
98 Downloads (Pure)

Abstract

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by recurrent mutations in genes encoding transcriptional, chromatin, and/or signaling regulators. The t(8;21) translocation generates the aberrant transcription factor RUNX1-ETO (RUNX1-RUNX1T1), which by itself is insufficient to cause disease. t(8;21) AML patients show extensive chromatin reprogramming and have acquired additional mutations. Therefore, the genomic and developmental effects directly and solely attributable to RUNX1-ETO expression are unclear. To address this, we employ a human embryonic stem cell differentiation system capable of forming definitive myeloid progenitor cells to express RUNX1-ETO in an inducible fashion. Induction of RUNX1-ETO causes extensive chromatin reprogramming by interfering with RUNX1 binding, blocks differentiation, and arrests cellular growth, whereby growth arrest is reversible following RUNX1-ETO removal. Single-cell gene expression analyses show that RUNX1-ETO induction alters the differentiation of early myeloid progenitors, but not of other progenitor types, indicating that oncoprotein-mediated transcriptional reprogramming is highly target cell specific.

Original languageEnglish
Article number107691
JournalCell Reports
Volume31
Issue number8
DOIs
Publication statusPublished - 26 May 2020

Bibliographical note

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords

  • Acute Myeloid Leukemia (AML)
  • RUNX1-ETO
  • chromatin
  • human ES cell differentiation
  • myelopoiesis
  • single cell RNA-Seq

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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