title: Predicting interactome network perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia.
abstract: Genomic variations such as point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and therapeutic targets. However, predicting the functional effect of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes are likely dependent of complex molecular interaction networks. Using as models three different chromosomal translocations-ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and TCF3-PBX1 (E2A-PBX1)-frequently found in precursor-B-cell acute lymphoblastic leukemia (preB-ALL), we develop an approach to extract perturbed molecular interactions from gene expression changes. We show that the MYC and JunD transcriptional circuits are specifically deregulated after ETV6-RUNX1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and ETV6-RUNX1 acute lymphoblastic leukemia.
authors.affiliation: Laboratoire de Bioinformatique des Génomes et des Réseaux, Université Libre de Bruxelles, B-1050 Bruxelles, Belgium.
authors.forename: Leon Juvenal
authors.initials: LJ
authors.lastname: Hajingabo
authors.affiliation: Laboratory of Protein Signaling and Interactions, GIGA-Research, University of Liège, B-4000 Liège, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Daakour
authors.affiliation: Laboratory of Protein Signaling and Interactions, GIGA-Research, University of Liège, B-4000 Liège, Belgium.
authors.forename: Maud
authors.initials: M
authors.lastname: Martin
authors.affiliation: Department of Biotechnology, University of Natural Resources and Life Sciences Vienna, 1180 Vienna, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Grausenburger
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, 1090 Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.affiliation: Laboratory of Protein Signaling and Interactions, GIGA-Research, University of Liège, B-4000 Liège, Belgium.
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.affiliation: Laboratoire de Bioinformatique des Génomes et des Réseaux, Université Libre de Bruxelles, B-1050 Bruxelles, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simonis
authors.affiliation: Laboratory of Protein Signaling and Interactions, GIGA-Research, University of Liège, B-4000 Liège, Belgium jean-claude.twizere@ulg.ac.be nicolassimonis@gmail.com.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Twizere
mesh_terms: D000465:Algorithms; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D050939:Gene Fusion; D053263:Gene Regulatory Networks / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016044:Fusion Proteins, bcr-abl; D015514:Oncogene Proteins, Fusion; C581634:BCR-ABL1 fusion protein, human; C543638:TCF3-PBX1 fusion protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein