title: CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia.
abstract: The most common rearrangement in childhood precursor B-cell acute lymphoblastic leukemia is the t(12;21)(p13;q22) translocation resulting in the ETV6-AML1 fusion gene. A frequent concomitant event is the loss of the residual ETV6 allele suggesting a critical role for the ETV6 transcriptional repressor in the etiology of this cancer. However, the precise mechanism through which loss of functional ETV6 contributes to disease pathogenesis is still unclear. To investigate the impact of ETV6 loss on the transcriptional network and to identify new transcriptional targets of ETV6, we used whole transcriptome analysis of both pre-B leukemic cell lines and patients combined with chromatin immunoprecipitation. Using this integrative approach, we identified 4 novel direct ETV6 target genes: CLIC5, BIRC7, ANGPTL2 and WBP1L To further evaluate the role of chloride intracellular channel protein CLIC5 in leukemogenesis, we generated cell lines overexpressing CLIC5 and demonstrated an increased resistance to hydrogen peroxide-induced apoptosis. We further described the implications of CLIC5's ion channel activity in lysosomal-mediated cell death, possibly by modulating the function of the transferrin receptor with which it colocalizes intracellularly. For the first time, we showed that loss of ETV6 leads to significant overexpression of CLIC5, which in turn leads to decreased lysosome-mediated apoptosis. Our data suggest that heightened CLIC5 activity could promote a permissive environment for oxidative stress-induced DNA damage accumulation, and thereby contribute to leukemogenesis.
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neveu
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.|Molecular biology program, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Spinella
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Richer
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Lagacé
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Pauline
authors.initials: P
authors.lastname: Cassart
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lajoie
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Silvana
authors.initials: S
authors.lastname: Jananji
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Drouin
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Healy
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Pathology and Cellular Biology, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Gilles R X
authors.initials: GR
authors.lastname: Hickson
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Canada daniel.sinnett@umontreal.ca.|Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montreal, Canada.|Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D018118:Chloride Channels; D006861:Hydrogen Peroxide; D008840:Microfilament Proteins; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C411466:CLIC5 protein, human