Doctoral thesis (Dissertations and theses)
Perturbations of interactome networks in acute lymphoblastic leukaemia: identification of EXT1 tumor suppressor as a Notch pathway regulator
Daakour, Sarah
2016
 

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Keywords :
acute lymphoblastic leukaemia; interactome; Notch pathway; cancer genes; EXT1
Abstract :
[en] Whole genome sequencing technologies have enabled the identification of mutations implicated in diseases including cancer. Recently, research efforts to compare and categorize mutations, genes expression and genomic characteristics helped generating literature-curation databases. A large number of databases were developed to address data integration and standardization for human cancers, such as Catalogue Of Somatic Mutations In Cancer (COSMIC), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, Integrative Onco Genomics (IntOGen). Although the identification of these mutations highlights “cancer causative genes”, it does not give a detailed explanation of molecular mechanisms leading to the development of cancer. Though, understanding mechanisms leading to cancer development and progression remains a challenge that requires further investigations. The great majority of mutated genes are found in liquid tumors such as leukemia and lymphomas. In the first part of this study, we reasoned that leukemia associated genes could be extended to additional candidates identified using interactomic approaches. We used protein-protein interaction (PPI) mapping strategies to explore information on cancer genes frequently mutated in Acute lymphoblastic leukemia (ALL). We first extracted mutational data associated to ALL, and used interactome mapping analysis for literature-curated interactions and yeast two-hybrid experimental data in order to identify potential novel target genes associated with ALL. We highlighted mutated hub proteins interconnected in an ALL-cancer gene products network and identified novel interacting partners that link key ALL-cancer driver gene products. We identified EXT1 tumor suppressor gene as a novel common interactor for NOTCH1 and FBXW7. In the second part of this study, we experimentally validated EXT1, as a novel player in the regulation of the Notch pathway. Our study thus provides a proof-of-concept on how systematic interactome approaches could allow identification of novel targeted genes and pathways associated to human cancer.
Research center :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Daakour, Sarah ;  Université de Liège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Biologie cell. et moléc.
Language :
English
Title :
Perturbations of interactome networks in acute lymphoblastic leukaemia: identification of EXT1 tumor suppressor as a Notch pathway regulator
Defense date :
10 March 2016
Number of pages :
141
Institution :
ULiège - Université de Liège
Degree :
doctorat en science: biochime, biologie moleculaire et cellulaire, bioinformatique et modélisation
Promotor :
Twizere, Jean-Claude  ;  Université de Liège - ULiège > Département GxABT > Microbial, food and biobased technologies
Piette, Jacques ;  Université de Liège - ULiège > GIGA > GIGA I3 - Virology and Immunology
President :
Dequiedt, Franck  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases
Jury member :
Simonis, Nicolas
salehi-Ashtiani, Kourosh
Manfroid, Isabelle ;  Université de Liège - ULiège > GIGA > GIGA Stem Cells - Zebrafish Development and Disease Model
Van Steen, Kristel  ;  Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Biostatistics, biomedicine and bioinformatics
Rezshoazy, René
Name of the research project :
perturbations of interactome networks in acute lymphoblastic leukaemia: identification of EXT1 timor suppressor as a Notch pathway regulator
Funders :
Télévie, Fonds Léon Frédéricq
Available on ORBi :
since 09 March 2016

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