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

Cell Reports (May 2020)

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

Affiliations

Monica Nafria: Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
Peter Keane: Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK
Elizabeth S. Ng: Murdoch Children’s Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia
Edouard G. Stanley: Murdoch Children’s Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia
Andrew G. Elefanty: Murdoch Children’s Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Constanze Bonifer: Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; Corresponding author

Journal volume & issue: Vol. 31, no. 8

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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