title: Unique long non-coding RNA expression signature in ETV6/RUNX1-driven B-cell precursor acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.|Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Ghazavi
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Annelynn
authors.initials: A
authors.lastname: Wallaert
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.|Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Hetty H
authors.initials: HH
authors.lastname: Helsmoortel
authors.affiliation: Department of Hemato-Oncology, HUDERF, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Alina
authors.initials: A
authors.lastname: Ferster
authors.affiliation: Department of Hematology, University Hospital Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Bakkus
authors.affiliation: Department of Hematology, Children's Hospital, Toulouse, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Plat
authors.affiliation: Department of Hematology, Institut Universitaire de Cancérologie de Toulouse, University Toulouse-III Paul-Sabatier, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Uyttebroeck
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Nieuwerburgh
authors.affiliation: Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Ghent University, Ghent, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Deforce
authors.affiliation: Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Lammens
authors.affiliation: Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D019295:Computational Biology / Q000379:methods; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D058977:Molecular Sequence Annotation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D062085:RNA, Long Noncoding; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein
keywords: BCP-ALL; ETV6/RUNX1; lncRNA