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
Autor: | Eamonn R. Maher, Farida Latif, Michael J. Griffiths, Anna T. Brini, Thomas L. Dunwell, Victoria K. Hill, Charles Craddock, Daniel Catchpoole, Dietmar Krex |
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Jazyk: | angličtina |
Rok vydání: | 2011 |
Předmět: |
Cancer Research
Tumor suppressor gene Biology Protein Serine-Threonine Kinases Epigenesis Genetic Acute lymphocytic leukemia Cell Line Tumor medicine Leukemia B-Cell Drosophila Proteins Humans Genes Tumor Suppressor Epigenetics Molecular Biology Regulation of gene expression Intracellular Signaling Peptides and Proteins Proteins DNA Methylation medicine.disease Phosphoproteins Neoplasm Proteins Gene Expression Regulation Neoplastic Leukemia ETV6 DNA methylation Acute Disease Cancer research Protein KIBRA Research Paper Signal Transduction |
Popis: | 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. |
Databáze: | OpenAIRE |
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