Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia
- Susanna Teppo1,7,
- Saara Laukkanen1,
- Thomas Liuksiala2,
- Jessica Nordlund3,
- Mikko Oittinen1,
- Kaisa J Teittinen1,
- Toni Grönroos1,
- Pascal St-Onge4,
- Daniel Sinnett5,
- Ann-Christine Syvänen3,
- Matti Nykter2,
- Keijo Viiri1,
- Merja Heinäniemi6 and
- Olli Lohi1
- 1 Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital;
- 2 Institute of Biosciences and Medical Technology, University of Tampere;
- 3 Molecular Medicine and Science for Life Laboratory, Uppsala Univ;
- 4 CHU Sainte-Justine Research Center, Université de Montréal;
- 5 Faculty of Medicine, Université de Montréal;
- 6 Institute of Biomedicine, School of Medicine, University of Eastern Finland
- ↵* Corresponding author; email: susanna.teppo{at}uta.fi
Abstract
Around 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 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 downregulated, 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.
- Received April 26, 2015.
- Accepted September 12, 2016.
- Published by Cold Spring Harbor Laboratory Press
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