Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencingof retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypo...

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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, Cervantes, F. (F.)|||/items/0aaaabf1-1d2b-4b46-a637-60a741307143, Sanchez, J. (Joaquín)|||/items/ca84b928-e80e-4b9b-b6d7-1d84bc313857, Garate-Iturriagagoitia, L. (Leire)|||/items/8cb76f28-d2ce-4a71-a8b9-3e3e37a120a3, Barrios, M. (M.)|||/items/b136d953-5bc8-42df-a21f-be09564d8fb8, Castillejo, J.A. (J.A.)|||/items/11701cff-259f-4b74-b164-9495896306f7, Navarro, G. (Germán)|||/items/b189b5d7-41ed-4f9b-8697-0958ddf51ccb, Colomer, D. (D.)|||/items/40229688-ee7e-47fe-86d7-1d8e9eb13044, 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:2005
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/18563
Acceso en línea:https://hdl.handle.net/10171/18563
Access Level:acceso abierto
Palabra clave:Hypomethylation
Retrotransposons
LINE-1
Blast crisis
Área de Terapia Celular
Descripción
Sumario:Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencingof retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronicphase (CP, n¼140) and the blast crisis (BC, n¼47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (Po0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (Po0.0001) and c-MET gene antisense transcription (Po0.0001), and was significantly associated with high levels of BCR–ABL (P¼0.02) and DNMT3b4 (P¼0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P¼0.004) or imatinib (P¼0.034) and progression-free survival (P¼0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.

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