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 is...

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Autores: Roman-Gomez, J. (José)|||/items/bca25c5c-f92e-4fe2-b9a3-4b722345de85, Jimenez-Velasco, A. (A.)|||/items/c56a1ba7-243e-4226-897d-6d969da1d058, Aguirre-Ena, X. (Xabier)|||/items/2a000d9c-cb5c-4734-a32c-4fef79998c86, Castillejo, J.A. (J.A.)|||/items/11701cff-259f-4b74-b164-9495896306f7, Navarro, G. (Germán)|||/items/b189b5d7-41ed-4f9b-8697-0958ddf51ccb, Barrios, M. (M.)|||/items/b136d953-5bc8-42df-a21f-be09564d8fb8, Andreu, E.J. (Enrique José)|||/items/bfb7adec-1ed3-4313-a2a7-8b026c48eba6, Prosper-Cardoso, F. (Felipe)|||/items/3d1b0b82-06c3-4e63-8280-e903dc4dc0c1, Heiniger, A. (A.)|||/items/c1560a2f-8133-4602-856c-ef23edb0a384, Torres, A. (Antonio)|||/items/2ef77e9e-4616-4a3a-b254-b11b17687f35
Tipo de recurso: artículo
Fecha de publicación:2004
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/17238
Acceso en línea:https://hdl.handle.net/10171/17238
Access Level:acceso abierto
Palabra clave:Acute lymphoblastic leukaemia
CpG island
Methylation
Dkk-3
Área de Terapia Celular
Descripción
Sumario: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.

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