title: Frequent epigenetic inactivation of KIBRA, an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia.
abstract: The WW-domain containing protein KIBRA has recently been identified as a new member of the Salvador/Warts/Hippo (SWH) pathway in Drosophila and is shown to act as a tumor suppressor gene in Drosophila. This pathway is conserved in humans and members of the pathway have been shown to act as tumor suppressor genes in mammalian systems. We determined the methylation status of the 5' CpG island associated with the KIBRA gene in human cancers. In a large panel of cancer cell lines representing common epithelial cancers KIBRA was unmethylated. But in pediatric acute lymphocytic leukemia (ALL) cell lines KIBRA showed frequent hypermethylation and silencing of gene expression, which could be reversed by treatment with 5-aza-2'-deoxycytidine. In ALL patient samples KIBRA was methylated in 70% B-ALL but was methylated in < 20% T-ALL leukemia (p = 0.0019). In B-ALL KIBRA methylation was associated with ETV6/RUNX1 [t(12;21) (p13;q22)] chromosomal translocation (p = 0.0082) phenotype, suggesting that KIBRA may play an important role in t(12;21) leukemogenesis. In ALL paired samples at diagnosis and remission KIBRA methylation was seen in diagnostic but not in any of the remission samples accompanied by loss of KIBRA expression in disease state compared to patients in remission. Hence KIBRA methylation occurs frequently in B-cell acute lymphocytic leukemia but not in epithelial cancers and is linked to specific genetic event in B-ALL.
authors.affiliation: Medical and Molecular Genetics, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Hill
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Dunwell
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpoole
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Anna T
authors.initials: AT
authors.lastname: Brini
authors.forename: Mike
authors.initials: M
authors.lastname: Griffiths
authors.forename: Charles
authors.initials: C
authors.lastname: Craddock
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D000208:Acute Disease; D045744:Cell Line, Tumor; D019175:DNA Methylation; D029721:Drosophila Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; C513637:WWC1 protein, human; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases