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

doi:10.1016/j.celrep.2020.107691

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

Cell Rep. 2020 May 26;31(8):107691. doi: 10.1016/j.celrep.2020.107691.

Authors

Monica Nafria¹, Peter Keane², Elizabeth S Ng³, Edouard G Stanley⁴, Andrew G Elefanty⁵, Constanze Bonifer⁶

Affiliations

¹ 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.
² Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
³ Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia.
⁴ 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.
⁵ 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. Electronic address: andrew.elefanty@mcri.edu.au.
⁶ Institute for Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.bonifer@bham.ac.uk.

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.

Keywords: Acute Myeloid Leukemia (AML); RUNX1-ETO; chromatin; human ES cell differentiation; myelopoiesis; single cell RNA-Seq.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Cell Proliferation
Chromatin / metabolism*
Core Binding Factor Alpha 2 Subunit / metabolism*
Humans
Myeloid Progenitor Cells / metabolism*

Substances

Chromatin
Core Binding Factor Alpha 2 Subunit
RUNX1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding