Unique long non-coding RNA expression signature in ETV6/RUNX1-driven B-cell precursor acute lymphoblastic leukemia
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Farzaneh Ghazavi1,2, Barbara De Moerloose1, Wouter Van Loocke2, Annelynn Wallaert2, Hetty H. Helsmoortel1,2, Alina Ferster3, Marleen Bakkus4, Geneviève Plat5, Eric Delabesse6, Anne Uyttebroeck7, Filip Van Nieuwerburgh8, Dieter Deforce8, Nadine Van Roy2, Frank Speleman2, Yves Benoit1, Tim Lammens1,*, Pieter Van Vlierberghe2,*
1Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
2Center for Medical Genetics, Department of Paediatrics and Genetics, Ghent University Hospital, Ghent, Belgium
3Department of Hemato-Oncology, HUDERF, Université Libre de Bruxelles (ULB), Brussels, Belgium
4Department of Hematology, University Hospital Brussels, Vrije Universiteit Brussel (VUB) Brussels, Belgium
5Department of Hematology, Children’s Hospital, Toulouse, France
6Department of Hematology, Institut Universitaire de Cancérologie de Toulouse, University Toulouse-III Paul-Sabatier, Toulouse, France
7Department of Pediatric Hemato-Oncology, University Hospitals Leuven, Belgium
8Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutics, Ghent University, Ghent, Belgium
*These authors have contributed equally to this work
Pieter Van Vlierberghe, email: [email protected]
Keywords: BCP-ALL, ETV6/RUNX1, LncRNA
Received: May 29, 2016 Accepted: September 02, 2016 Published: September 16, 2016
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.
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