Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia

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 i...

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Bibliographic Details
Published in:British journal of cancer 2004-08, Vol.91 (4), p.707-713
Main Authors: ROMAN-GOMEZ, J, JIMENEZ-VELASCO, A, AGIRRE, X, CASTILLEJO, J. A, NAVARRO, G, BARRIOS, M, ANDREU, E. J, PROSPER, F, HEINIGER, A, TORRES, A
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Adolescent
Adult
Aged
Aged, 80 and over
Biological and medical sciences
Cancer research
Cell Transformation, Neoplastic
Chemokines
Child
Child, Preschool
Chromosomes
Chromosomes, Human, Pair 11 - genetics
CpG Islands
DNA Methylation
DNA, Neoplasm - metabolism
Female
Gene expression
Gene Silencing
Hematologic and hematopoietic diseases
Humans
Infant
Intercellular Signaling Peptides and Proteins
Leukemia
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical prognosis
Medical research
Medical sciences
Middle Aged
Molecular and Cellular Pathology
Molecular biology
Multivariate Analysis
Pathogenesis
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Prognosis
Promoter Regions, Genetic
Protein Biosynthesis
Proteins - genetics
Survival Analysis
Transcription, Genetic
Tumor Cells, Cultured
Tumors
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Summary: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 (P=0.001 and 0.09). Multivariate analysis demonstrated that Dkk-3 methylation was an independent prognostic factor predicting DFS (P=0.0009). Our data suggest that Dkk-3 methylation occurs at an early stage in ALL pathogenesis and probably influences the clinical behaviour of the disease.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6602008