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Genome Res. 2016 Nov;26(11):1468-1477. Epub 2016 Sep 12.

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia.

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Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Institute of Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland.
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada.
Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada.
Department of Signal Processing, Tampere University of Technology, 33720 Tampere, Finland.
Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.


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.

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