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

A Retraction to this article was published on 07 February 2013

Abstract

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 silencing of 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 chronic-phase (CP, n=140) and the blast crisis (BC, n=47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (P<0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (P<0.0001) and c-MET gene antisense transcription (P<0.0001), and was significantly associated with high levels of BCR–ABL (P=0.02) and DNMT3b4 (P=0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P=0.004) or imatinib (P=0.034) and progression-free survival (P=0.005). 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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Acknowledgements

This work was supported by grants from Fondo de Investigacion Sanitaria (FIS, Spain) 03/0141, 01/0013-01, 01/F018, 02/1299; Navarra Goverment (31/2002); RETIC C03/10, Junta de Andalucia 03/143; 03/144, and funds from Cajamar-Fundacion Hospital Carlos Haya (IMABIS, Malaga, Spain), ‘UTE project CIMA’, Fundación de Investigación Médica Mutua Madrileña Automovilista and Asociacion Medicina e Investigacion (AMI).

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Correspondence to Jose Roman-Gomez.

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Roman-Gomez, J., Jimenez-Velasco, A., Agirre, X. et al. Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia. Oncogene 24, 7213–7223 (2005). https://doi.org/10.1038/sj.onc.1208866

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Keywords

  • CML
  • hypomethylation
  • retrotransposons
  • LINE-1
  • blast crisis

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