Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia
- Susanna Teppo1,
- Saara Laukkanen1,
- Thomas Liuksiala1,2,
- Jessica Nordlund3,
- Mikko Oittinen1,
- Kaisa Teittinen1,
- Toni Grönroos1,
- Pascal St-Onge4,
- Daniel Sinnett4,5,
- Ann-Christine Syvänen3,
- Matti Nykter2,6,
- Keijo Viiri1,
- Merja Heinäniemi7,8 and
- Olli Lohi1,8
- 1Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland;
- 2Institute of Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland;
- 3Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden;
- 4CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada;
- 5Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada;
- 6Department of Signal Processing, Tampere University of Technology, 33720 Tampere, Finland;
- 7Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland
- Corresponding author: susanna.teppo{at}uta.fi
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↵8 Co-senior authors.
Abstract
Approximately 20%–25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif–containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19+/CD20+-lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.193649.115.
- Received April 26, 2015.
- Accepted September 12, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
