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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.

Author information

1
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
2
Institute of Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland.
3
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
4
CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada.
5
Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada.
6
Department of Signal Processing, Tampere University of Technology, 33720 Tampere, Finland.
7
Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.

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.

PMID:
27620872
PMCID:
PMC5088590
DOI:
10.1101/gr.193649.115
[Indexed for MEDLINE]
Free PMC Article

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