Unique long non-coding RNA expression signature in ETV6/RUNX1-driven B-cell precursor acute lymphoblastic leukemia

// Farzaneh Ghazavi 1, 2 , Barbara De Moerloose 1 , Wouter Van Loocke 2 , Annelynn Wallaert 2 , Hetty H. Helsmoortel 1, 2 , Alina Ferster 3 , Marleen Bakkus 4 , Genevieve Plat 5 , Eric Delabesse 6 , Anne Uyttebroeck 7 , Filip Van Nieuwerburgh 8 , Dieter Deforce 8 , Nadine Van Roy 2 , Frank Speleman 2 , Yves Benoit 1 , Tim Lammens 1, * , Pieter Van Vlierberghe 2, * 1 Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium 2 Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium 3 Department of Hemato-Oncology, HUDERF, Universite Libre de Bruxelles (ULB), Brussels, Belgium 4 Department of Hematology, University Hospital Brussels, Vrije Universiteit Brussel (VUB) Brussels, Belgium 5 Department of Hematology, Children’s Hospital, Toulouse, France 6 Department of Hematology, Institut Universitaire de Cancerologie de Toulouse, University Toulouse-III Paul-Sabatier, Toulouse, France 7 Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Belgium 8 Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Ghent University, Ghent, Belgium * These authors have contributed equally to this work Correspondence to: Pieter Van Vlierberghe, email: pieter.vanvlierberghe@ugent.be Keywords: BCP-ALL, ETV6/RUNX1, LncRNA Received: May 29, 2016      Accepted: September 02, 2016      Published: September 16, 2016 ABSTRACT Overwhelming evidence indicates that long non-coding RNAs have essential roles in tumorigenesis. Nevertheless, their role in the molecular pathogenesis of pediatric B-cell precursor acute lymphoblastic leukemia has not been extensively explored. Here, we conducted a comprehensive analysis of the long non-coding RNA transcriptome in ETV6/RUNX1-positive BCP-ALL, one of the most frequent subtypes of pediatric leukemia. First, we used primary leukemia patient samples to identify an ETV6/RUNX1 specific expression signature consisting of 596 lncRNA transcripts. Next, integration of this lncRNA signature with RNA sequencing of BCP-ALL cell lines and lncRNA profiling of an in vitro model system of ETV6/RUNX1 knockdown, revealed that lnc-NKX2-3-1 , lnc-TIMM21-5, lnc-ASTN1-1 and lnc-RTN4R-1 are truly regulated by the oncogenic fusion protein. Moreover, sustained inactivation of lnc-RTN4R-1 and lnc-NKX2-3-1 in ETV6/RUNX1 positive cells caused profound changes in gene expression. All together, our study defined a unique lncRNA expression signature associated with ETV6/RUNX1-positive BCP-ALL and identified lnc-RTN4R-1 and lnc-NKX2-3-1 as lncRNAs that might be functionally implicated in the biology of this prevalent subtype of human leukemia.