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

Research output: Contribution to journalArticle

Authors

  • Monica Nafria
  • Elizabeth S Ng
  • Edouard G Stanley
  • Andrew G Elefanty

Colleges, School and Institutes

External organisations

  • Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health
  • Murdoch Children's Research Institute, Level 4 West, Royal Children's Hospital Melbourne
  • Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

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.

Bibliographic note

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

Details

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

Keywords

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