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CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)

Written2005-10Anthony J Bais
Department of Haematology, Genetic Pathology, Flinders University, Bedford Park, Adelaide, SA 5042, Australia

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Other namesMTG16
LocusID (NCBI) 863
Atlas_Id 428
Location 16q24.3  [Link to chromosome band 16q24]
Location_base_pair Starts at 88941263 and ends at 89043504 bp from pter ( according to hg19-Feb_2009)  [Mapping CBFA2T3.png]
Local_order telomere; centromeric to CDH15 and telomeric to GALNS
Fusion genes
(updated 2016)
CBFA2T3 (16q24.3) / BLOC1S1 (12q13.2)CBFA2T3 (16q24.3) / GALNS (16q24.3)CBFA2T3 (16q24.3) / GLIS2 (16p13.3)
CBFA2T3 (16q24.3) / RUNX1 (21q22.12)IGH (14q32.33) / CBFA2T3 (16q24.3)KCNIP2 (10q24.32) / CBFA2T3 (16q24.3)
MAP4 (3p21.31) / CBFA2T3 (16q24.3)NFIA (1p31.3) / CBFA2T3 (16q24.3)PIEZO1 (16q24.3) / CBFA2T3 (16q24.3)
RUNX1 (21q22.12) / CBFA2T3 (16q24.3)


Description CBFA2T3 encodes two alternative transcripts, CBFA2T3A and CBFA2T3B, via the use of alternative start sites at exons 1A and 1B, respectively.
  • CBFA2T3A is 4,265-bp in length, composed of 13 exons (1A and 2 to 12) spanning approximately 130-kb of genomic DNA, and has an ORF of 1,959-bp encoding a protein of 653 amino acids.
  • CBFA2T3B is 4,034-bp in length, composed of 12 exons (1B to 12 splicing out exon 3) spanning approximately 50-kb of genomic DNA, and has an ORF of 1,701-bp encoding a protein of 567 amino acids.
  • Additional CBFA2T3C and CBFA2T3D isoforms have been identified in leukemic and HEL cell lines. CBFA2T3C encodes a protein that lacks exons 2 and 3, and CBFA2T3D is a truncated protein with out-of-frame splicing of exon 1A to exon 5.
  • The CBFA2T3A open-reading-frame (ORF) may include an additional 177 amino acids beyond the originally proposed methionine start codon.
  • The CBFA2T3B isoform contains a high-density 1-kb CpG island within and five prime to the exon 1B start site.
  • A hypothetical protein FLJ26728 located within and proximal to the CpG island transcribes antisense to CBFA2T3. Another hypothetical protein FLJ23429 transcribes antisense starting from within the first alternative intron.
  • Pseudogene None identified.


    Description ETO proteins are composed of four evolutionarily conserved domains termed nervy homology regions (NHR1 to 4) and three proline-serine-threonine (PST) rich regions. The fourth NHR region is also referred to as the zinc-finger MYND (zf myeloid-nervy-DEAF-1) domain.
  • NHR1 shares significant homology to human TATA-binding protein (TBP)-associated factor 130 (hTAF 130), hTAF 105, Drosophila accessory or activation factor TAF 110, and is often referred to as the TAF 110 domain.
  • NHR2 is a small region containing homo and heterodimerization domains and a hydrophobic heptad repeat (HHR) unit.
  • The sequence of NHR3 is unremarkable in homology and often referred to as the nervy domain.
  • The C-terminal NHR4 domain exists in numerous human, murine, Caenorhabditis elegans and Drosophila proteins, and contains a MYND zinc-finger motif. The motif is composed of CXXC and two (C-H)XXXC regions which correspond to cysteine-histidine 'knuckle structures' that are the basic building blocks of many zinc-finger proteins. The zinc-finger is common to the developmental proteins rat programmed cell death (RP-8), the human homolog programmed cell death 2 (PDCD2), deformed epidermal autoregulatory factor-1 (DEAF-1), suppressin (SPN), BLU or zinc-finger MYND domain containing 10 (ZMYND10), adenovirus 5 E1A binding protein (BS69), and CD8 beta opposite (BOP).
  • Expression CBFA2T3 is widely expressed in B-cells, blood, brain, breast, cervix, colon, eye, kidney tumor, lymph, marrow, muscle, pancreas, placenta and tonsil. CBFA2T3 exists predominantly as 4.5 and 4.2-kb transcripts along with several other minor RNAs in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte.
    Localisation All ETO members contain nuclear localization signals (NLS), some of which may be abrogated through five prime variations to enable extracellular targeting. For instance, CBFA2T1 has been detected in the cytoplasm of Purkinje cells in adult human brain, and both CBFA2T1 and CBFA2T3B have been detected in the Golgi apparatus, where they may function as cAMP-dependent protein kinase anchoring proteins. The majority of ETO proteins presumably remain in the nucleus for transcriptional regulation.
    Function CBFA2T3 has been considered to function as a transcriptional repressor via interaction with corepressor complexes.
  • The CBFA2T3A isoform oligomerizes and drags MTG8 and MTGR1 to the nucleus, oligomerizes with RUNX1-MTG16 fusion proteins in the nucleoplasm, interacts with nuclear HDACs 1 and 3, and when overexpressed accumulates at the periphery of nucleoli in characteristic rings. Because clustered arrays of inactive methylated ribosomal DNA (rDNA) repeats are also found at the nucleoli periphery, it has been speculated that CBFAT23A could be involved in methylation silencing of rDNA in the nucleolus.
  • The CBFA2T3B isoform has been shown to function in T lymphocytes as a kinase anchorage protein, and interact with cyclic nucleotide phosphodiesterases, suggesting it may function in T cell activation and inflammatory response. CBFA2T3B has been shown to function as a transcriptional repressor when tethered to a GAL4 DNA-binding domain in gene reporter assays, and inhibit the growth of breast tumor cell lines with reduced expression when ectopically expressed using retrovirus.

    CBFA2T3 has been found to interact with a novel zinc finger protein KIA00924 to mediate potent transcriptional repression as determined by CAT reporter gene assays. The presence of a zinc-finger motif common to developmental proteins suggests that CBFA2T3 might function in regulating differentiation and morphogenesis. The RP-8 and human homolog PDCD2 proteins assume a role in programmed cell death, a process essential for epithelial turnover. DEAF-1 is essential for early embryonic dorsal epidermal, eye and wing development in Drosophila. BOP encodes a muscle-restricted protein essential for cardiomyocyte differentiation and morphogenesis. BLU is a candidate tumor suppressor gene from the 3p21.3 LOH region in many human cancers, and SPN from rat functions as a potent tumor suppressor of leukemia, lymphoma and thymoma cells and tumor cells from the brain, breast, pituitary and adrenal glands.
    CBFA2T3 transcripts of CD34(+) progenitor cells have been shown to be rapidly reduced by cytokine-induced differentiation into myeloid or erythroid lineages, supporting suggestion that CBFA2T3 may function in hematopoietic differentiation. The CBFA2T3B CpG island contains several Specificity protein 1 (Sp1), homeotic, epidermal and insulin growth factor recognition sites. High conserved binding sites include GATA-1, CREB, F-1 and PKNOX1.

  • Homology The human gene CBFA2T3 is a member of the eight-twenty-one (ETO) family of proteins. The human ETO family consists of the ETO gene, also known as the myeloid translocation gene 8 (MTG8, CBFA2T1), the myeloid translocation gene related protein-1 (EHT, MTGR1, CBFA2T2), and the myeloid translocation gene 16 (MTG16, MTGR2, ZMYND4, HGNC:1537, CBFA2T3).
    Murine homologs of the ETO family include mETO (cbfa2t1h), ET0-2 (cbfa2t3h), and cbfa2t2h, the latter of which is uncharacterised. Chicken cETO and Drosophila nervy homologs have also been identified.
    The ETO protein family members and NHRs are highly homologous and conserved to each other. The CBFA2T3A and B isoforms share significant homology to MTG8 (67 and 75%, respectively) and MTGR1 (54 and 61%, respectively), and approximately 30% homology to nervy. CBFA2T3 shares 86% homology to the murine ETO-2 (cbfa2t3h), which in turn shares 75 and 60% homology to MTG8 and MTGR1, respectively, suggesting that ETO-2 is the murine homolog of CBFA2T3. MTG8 is approximately 99, 65 and 30% homologous to murine ETO, MTGR1 and nervy, respectively.


    Note None recorded.

    Implicated in

    Entity t(16;21)(q24;q22) in therapy related acute myeloid leukemia (t-AML) --> CBFA2T3/ RUNX1
    Note CBFA2T3 or MTG16 was identified by molecular characterization of a second less common therapy-related AML translocation involving t(16;21). Characterization of the t(16;21) demonstrated that RUNX1-MTG16 fusion transcripts similar to RUNX1-ETO were generated
    Abnormal Protein
  • The RUNX1-MTG8, and to a lesser extent the RUNX1-MTG16, fusion transcripts of the t(8;21)(q22;q22) and t(16;21) events are most recognized for their ability to function as transcriptional repressors of genes normally activated by RUNX1 through their interaction with corepressor complexes involving N-CoR, mSin3A, SMRT, and HDACs.
  • The MTG8 or CBFA2T1 gene is the most studied member of the ETO family and is additionally recognized for its ability to function independently as a nuclear transcriptional repressor through nuclear corepressor complex interaction. Gene targeting experiments demonstrating that homozygous mutant mice with an inactivating insertion of LacZ in exon 2 of the MTG8 locus resulted in massive gastrointestinal defects, have also shown that MTG8 and perhaps ETO family members are essential for gastrointestinal development .
  • Multiple NHRs of the ETO family of proteins are required and cooperate to mediate transcriptional repression. Most of the proteins that interact with NHRs have been assigned from studies of RUNX1-MTG8 and its interacting proteins. Studies originally demonstrated that MTG8s NHR2 and NHR4 were required for AML-MTG8 to inhibit RUNX1 mediated transcriptional activation and initiated the search for 'corepressor complexes' that bind to these regions. Several yeast two-hybrid systems using portions of MTG8 as bait demonstrated that specific portions of NHR2, NHR3 and NHR4 interact with the human nuclear receptor co-repressor (HuN-CoR)-mSin3A-HDAC1 corepressor complex.
  • The N-CoR protein was originally described to interact with DNA-bound nuclear receptors to repress transcription of target genes through recruitment of HDAC containing complexes and was latter shown to form complexes with mammalian Sin3 to alter chromatin structure and mediate transcriptional repression via nuclear receptors and oncoregulatory proteins.
  • A similar yeast two-hybrid approach also established that the corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) interacts with MTG8. The zinc-finger NHR4 is necessary but not sufficient for repression and interaction with SMRT and N-CoR in vitro. The direct physical association of MTG8 with corepressors is more complex. A 'core-repressor domain' containing NHR2 and the neighboring amino and carboxy terminal sequences was defined and found to be the strongest region of interaction with mSin3a and transcriptional repression.
  • In the RUNX1-MTG8 translocation product associated with myeloid malignancies, the transactivation domain of the RUNX1 gene, which normally binds the transcriptional coactivators p300-CBP, is replaced by almost the entire MTG8 protein. The resultant fusion protein recruits a corepressor complex containing HDAC activity instead of the coactivators p300-CBP to RUNX1 responsive genes giving rise to leukemia. The repression activity of the MTG8 protein was demonstrated from a GAL4 DNA binding domain (DBD) MTG8 fusion construct which mediated strong repression through multimerized GAL4 binding sites upstream of a minimal promoter driving a reporter gene. Consistent with a mechanism involving MTG8 and HDAC corepressor interactions, the repressive effect of MTG8 was partially overcome with the addition of the HDAC inhibitor trichostatin A (TSA). Mutational studies of RUNX1-MTG8 have shown that NHR4 is responsible for repression of the multidrug resistance 1 promoter.
  • MTG8 has also been shown to interact with the Dentato-rubral and Pallido-luysian atrophy gene product, atrophin-1, in a yeast two-hybrid assay. Both Dentato-rubral and Pallido-luysian atrophies are neurodegenerative disorders caused by expansion of polyglutamine tracts.
  • Several other transcriptional repressors have been shown to interact with MTG8. The promyelocytic leukemia zinc-finger ( PLZF), a transcriptional repressor found in hematopoietic cells and down-regulated during differentiation of myeloid cell lines was shown to exhibit enhanced repressor activity when interacting with MTG8 in 293T cells and assayed using a reporter plasmid containing four copies of a high affinity PLZF binding site linked to firefly luciferase. The ability of MTG8 to enhance repression was abolished upon addition of HDAC inhibitors TSA and sodium butyrate, suggesting that the MTG8 enhanced repression by PLZF is also mediated through the recruitment of HDACs.
  • The Growth factor independence-1 (Gfi-1), a HDAC interacting transcriptional repressor found in hematopoietic cells, was shown in vitro and in vivo to interact with NHR1 and NHR2 of MTG8. These interactions together with gene targeting experiments demonstrating MTG8s involvement in gastrointestinal development, the well established interactions with corepressor complexes, and the presence of a zinc-finger motif common to numerous developmental proteins, suggests that ETO family members including CBFA2T3 may play function in regulating cell cycle transcription during differentiation and proliferation of specific cell type-lineages, for example hematopoietic cells as indicated for MTG8.
    Entity Loss of heterozygosity (LOH) of 16q22-qter in breast cancer, prostate cancer, and several other cancers
    Note This region is frequently deleted in several human cancers causing loss of heterozygosity. The 16q24.3 region including CBFA2T3 spans approximately 3-Mb from the marker D16S498 to the telomere and contains at least two smallest regions of overlap (SROs). These SROs are most frequently deleted in early and late stage breast cancer and in prostate cancer. Loss of normal function of CBFA2T3 may be a key event in the early stage of breast cancer. LOH on the whole 16q22-qter region is frequently detected in breast and prostate cancer.
    CBFA2T3B is a potential tumor suppressor gene affected by LOH, aberrant gene expression and promoter methylation in breast cancer. Quantitative gene expression analysis of 78 genes in the 16q24.3 region demonstrated that CBFA2T3 was the only gene with an aberrant expression profile distinctly similar to the known tumor suppressors SYK and CDKN2A. 68 genes displayed normal expression, six displayed mildly aberrant expression (DPEP1, CDH15, Hs.17074, Hs.189419, SLC7A5 and AA994450), one displayed excessively reduced expression (CA5A), and two displayed moderately aberrant expression (CYBA and FBX031). The CBFA2T3B promoter region displays aberrant hypo and hypermethylation in breast tumor cell lines and primary breast tumor samples in correlation with aberrant gene expression.
    Disease 16q22-qter LOH is detected in bilateral breast cancer and ductal lavage, in rare inflammatory breast cancer, and in several other cancers, including central nervous system neuroectodermal and primary ependymomas, colorectal liver metastases, gastric tumor, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung tumor, nasopharyngeal tumor, ovarian tumor, rhabdomyosarcoma, and Wilms' tumor. 16q22-qter LOH in ovarian, hepatocellular and particularly breast and prostate cancers, exhibit similar SROs, suggesting common molecular pathways are affected.


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    This paper should be referenced as such :
    Bais, AJ
    CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):70-76.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
      21q22 rearrangements (RUNX1) in treatment related leukemia
    inv(16)(p13q24) CBFA2T3/GLIS2
    t(16;21)(q24;q22) RUNX1/CBFA2T3

    External links

    HGNC (Hugo)CBFA2T3   1537
    Entrez_Gene (NCBI)CBFA2T3  863  CBFA2/RUNX1 translocation partner 3
    AliasesETO2; MTG16; MTGR2; RUNX1T3; 
    GeneCards (Weizmann)CBFA2T3
    Ensembl hg19 (Hinxton)ENSG00000129993 [Gene_View]  chr16:88941263-89043504 [Contig_View]  CBFA2T3 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000129993 [Gene_View]  chr16:88941263-89043504 [Contig_View]  CBFA2T3 [Vega]
    ICGC DataPortalENSG00000129993
    TCGA cBioPortalCBFA2T3
    AceView (NCBI)CBFA2T3
    Genatlas (Paris)CBFA2T3
    SOURCE (Princeton)CBFA2T3
    Genetics Home Reference (NIH)CBFA2T3
    Genomic and cartography
    GoldenPath hg19 (UCSC)CBFA2T3  -     chr16:88941263-89043504 -  16q24   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)CBFA2T3  -     16q24   [Description]    (hg38-Dec_2013)
    EnsemblCBFA2T3 - 16q24 [CytoView hg19]  CBFA2T3 - 16q24 [CytoView hg38]
    Mapping of homologs : NCBICBFA2T3 [Mapview hg19]  CBFA2T3 [Mapview hg38]
    Gene and transcription
    Genbank (Entrez)AB010419 AB010420 AF052220 AK090985 AK097904
    RefSeq transcript (Entrez)NM_005187 NM_175931
    RefSeq genomic (Entrez)NC_000016 NC_018927 NG_029533 NT_010498 NW_004929403
    Consensus coding sequences : CCDS (NCBI)CBFA2T3
    Cluster EST : UnigeneHs.513811 [ NCBI ]
    CGAP (NCI)Hs.513811
    Alternative Splicing GalleryENSG00000129993
    Gene ExpressionCBFA2T3 [ NCBI-GEO ]   CBFA2T3 [ EBI - ARRAY_EXPRESS ]   CBFA2T3 [ SEEK ]   CBFA2T3 [ MEM ]
    Gene Expression Viewer (FireBrowse)CBFA2T3 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)863
    GTEX Portal (Tissue expression)CBFA2T3
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtO75081 (Uniprot)
    NextProtO75081  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProO75081
    Splice isoforms : SwissVarO75081 (Swissvar)
    Domaine pattern : Prosite (Expaxy)TAFH (PS51119)    ZF_MYND_1 (PS01360)    ZF_MYND_2 (PS50865)   
    Domains : Interpro (EBI)CBFA2T1/2/3    MTG16    NHR2    TAFH_NHR1    Znf_MYND   
    Domain families : Pfam (Sanger)NHR2 (PF08788)    TAFH (PF07531)    zf-MYND (PF01753)   
    Domain families : Pfam (NCBI)pfam08788    pfam07531    pfam01753   
    Domain families : Smart (EMBL)TAFH (SM00549)  
    DMDM Disease mutations863
    Blocks (Seattle)CBFA2T3
    Human Protein AtlasENSG00000129993
    Peptide AtlasO75081
    IPIIPI00306845   IPI00640985   IPI00218436   IPI00869145   IPI00868925   IPI00021473   IPI01018960   
    Protein Interaction databases
    DIP (DOE-UCLA)O75081
    IntAct (EBI)O75081
    Ontologies - Pathways
    Ontology : AmiGOGolgi membrane  response to hypoxia  transcription factor activity, sequence-specific DNA binding  transcription corepressor activity  protein binding  nucleus  nucleus  nucleoplasm  nucleolus  transcription, DNA-templated  cell proliferation  negative regulation of cell proliferation  granulocyte differentiation  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  negative regulation of glycolytic process  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  metal ion binding  regulation of aerobic respiration  
    Ontology : EGO-EBIGolgi membrane  response to hypoxia  transcription factor activity, sequence-specific DNA binding  transcription corepressor activity  protein binding  nucleus  nucleus  nucleoplasm  nucleolus  transcription, DNA-templated  cell proliferation  negative regulation of cell proliferation  granulocyte differentiation  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  negative regulation of glycolytic process  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  metal ion binding  regulation of aerobic respiration  
    NDEx NetworkCBFA2T3
    Atlas of Cancer Signalling NetworkCBFA2T3
    Wikipedia pathwaysCBFA2T3
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000129993
    Phylogenetic Trees/Animal Genes : TreeFamCBFA2T3
    Homologs : HomoloGeneCBFA2T3
    Homology/Alignments : Family Browser (UCSC)CBFA2T3
    Gene fusions - Rearrangements
    Fusion : MitelmanCBFA2T3/GLIS2 [16q24.3/16p13.3]  
    Fusion : MitelmanIGH/CBFA2T3 [14q32.33/16q24.3]  [t(14;16)(q32;q24)]  
    Fusion : MitelmanNFIA/CBFA2T3 [1p31.3/16q24.3]  [t(1;16)(p31;q24)]  
    Fusion : MitelmanPIEZO1/CBFA2T3 [16q24.3/16q24.3]  [t(16;16)(q24;q24)]  
    Fusion : MitelmanRUNX1/CBFA2T3 [21q22.12/16q24.3]  [t(16;21)(q24;q22)]  
    Fusion: TCGAFAM38A CBFA2T3 16q24.3 OV
    Fusion : TICdbRUNX1 [21q22.12]  -  CBFA2T3 [16q24.3]
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerCBFA2T3 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)CBFA2T3
    Exome Variant ServerCBFA2T3
    ExAC (Exome Aggregation Consortium)CBFA2T3 (select the gene name)
    Genetic variants : HAPMAP863
    Genomic Variants (DGV)CBFA2T3 [DGVbeta]
    DECIPHER (Syndromes)16:88941263-89043504  ENSG00000129993
    CONAN: Copy Number AnalysisCBFA2T3 
    ICGC Data PortalCBFA2T3 
    TCGA Data PortalCBFA2T3 
    Broad Tumor PortalCBFA2T3
    OASIS PortalCBFA2T3 [ Somatic mutations - Copy number]
    Cancer Gene: CensusCBFA2T3 
    Somatic Mutations in Cancer : COSMICCBFA2T3 
    Mutations and Diseases : HGMDCBFA2T3
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch CBFA2T3
    DgiDB (Drug Gene Interaction Database)CBFA2T3
    DoCM (Curated mutations)CBFA2T3 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)CBFA2T3 (select a term)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Genetic Testing Registry CBFA2T3
    NextProtO75081 [Medical]
    Huge Navigator CBFA2T3 [HugePedia]
    snp3D : Map Gene to Disease863
    BioCentury BCIQCBFA2T3
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD863
    Chemical/Pharm GKB GenePA26113
    Clinical trialCBFA2T3
    canSAR (ICR)CBFA2T3 (select the gene name)
    PubMed39 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

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    indexed on : Mon Oct 10 11:33:48 CEST 2016

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