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Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia
- Source :
- Dadun. Depósito Académico Digital de la Universidad de Navarra, instname, Europe PubMed Central, British Journal of Cancer
- Publication Year :
- 2004
- Publisher :
- H K Lewis and Co, Ltd., 2004.
-
Abstract
- Dkk-3 is a newly characterised mortalisation-related gene and an antagonist of the Wnt oncogenic signalling pathway whose expression is decreased in a variety of cancer cell lines, suggesting that the Dkk-3 gene, located at chromosome 11p15.1, functions as a tumour suppressor gene. Although 11p15 is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia (ALL), the role of Dkk-3 abnormalities has never been evaluated in this disease. We analysed CpG island methylation of the Dkk-3 promoter in six ALL cell lines and 183 ALL patients. We observed Dkk-3 hypermethylation in all cell lines and in cells from 33% (60/183) of ALL patients. Moreover, Dkk-3 methylation was associated with decreased Dkk-3 mRNA expression and this expression was restored after exposure to the demethylating agent 5-AzaC. Clinical features did not differ between hypermethylated and unmethylated patients. Estimated disease-free survival (DFS) and overall survival at 10 and 11 years, respectively, were 49.8 and 45.6% for normal patients and 10.5 and 15.1% for hypermethylated patients (P¼0.001 and 0.09). Multivariate analysis demonstrated that Dkk-3 methylation was an independent prognostic factor predicting DFS (P¼0.0009). Our data suggest that Dkk-3 methylation occurs at an early stage in ALL pathogenesis and probably influences the clinical behaviour of the disease.
- Subjects :
- Male
Cancer Research
Transcription, Genetic
acute lymphoblastic leukaemia
chemistry.chemical_compound
Tumor Cells, Cultured
Child
Promoter Regions, Genetic
Aged, 80 and over
Acute lymphoblastic leukaemia
Wnt signaling pathway
DNA, Neoplasm
Methylation
Middle Aged
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Prognosis
Cell Transformation, Neoplastic
Oncology
CpG site
Child, Preschool
DNA methylation
Intercellular Signaling Peptides and Proteins
Female
Chemokines
Dkk-3
Adult
Adolescent
Biology
Acute lymphocytic leukemia
medicine
Humans
Gene silencing
Gene Silencing
Gene
Adaptor Proteins, Signal Transducing
Aged
Chromosomes, Human, Pair 11
Molecular and Cellular Pathology
Infant
Proteins
DNA Methylation
medicine.disease
Survival Analysis
Molecular biology
Demethylating agent
chemistry
Protein Biosynthesis
Multivariate Analysis
CpG island
CpG Islands
methylation
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Dadun. Depósito Académico Digital de la Universidad de Navarra, instname, Europe PubMed Central, British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....c2ea57faf0cc40f2b75f2d2a09e8686e