Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia.
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.
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Susanna
0000-0003-2569-8030
S
Teppo
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Saara
S
Laukkanen
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.
Thomas
T
Liuksiala
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
Jessica
J
Nordlund
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Mikko
M
Oittinen
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Kaisa
K
Teittinen
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Toni
T
Grönroos
CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, H3T 1J4, Canada.
Pascal
P
St-Onge
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.
Daniel
D
Sinnett
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
Ann-Christine
AC
Syvänen
Institute of Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland.|Department of Signal Processing, Tampere University of Technology, 33720 Tampere, Finland.
Matti
M
Nykter
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Keijo
K
Viiri
Institute of Biomedicine, School of Medicine, University of Eastern Finland, 70211 Kuopio, Finland.
Merja
0000-0001-6190-3439
M
Heinäniemi
Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.
Olli
0000-0001-9195-0797
O
Lohi
D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein