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

Susanna Teppo, Saara Laukkanen, Thomas Liuksiala, Jessica Nordlund, Mikko Oittinen, Kaisa Teittinen, Toni Grönroos, Pascal St-Onge, Daniel Sinnett, Ann-Christine Syvänen, Matti Nykter, Keijo Viiri, Merja Heinäniemi, Olli Lohi

Research output: Contribution to journalArticleScientificpeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1468-1477
Number of pages10
JournalGenome Research
Volume26
Issue number11
DOIs
Publication statusPublished - 2016
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 3

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