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Acute Leukemias

Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia

Leukemia volume 24, pages 932–941 (2010)Cite this article

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Abstract

This study was designed to analyze the effect of global and gene-specific DNA methylation patterns on the outcome of patients with acute myeloid leukemia (AML). Methylation of CDKN2B (p15), E-cadherin (CDH) and hypermethylated in cancer 1 (HIC1) promoters and global DNA methylation by luminometric methylation assay (LUMA) was analyzed in 107 AML patients and cytogenetic and molecular mutational analysis was performed. In addition, genome-wide promoter-associated methylation was assessed using the Illumina HumanMethylation27 array in a proportion of the patients. Promoter methylation was discovered in 66, 66 and 51% of the patients for p15, CDH and HIC1, respectively. In multivariate analysis, low global DNA methylation was associated with higher complete remission rate (hazard ratio (HR) 5.9, P=0.005) and p15 methylation was associated with better overall (HR 0.4, P=0.001) and disease-free survival (HR 0.4, P=0.016). CDH and HIC1 methylation were not associated with clinical outcome. Mutational status and karyotype were not significantly associated with gene-specific methylation or global methylation. Increased genome-wide promoter-associated methylation was associated with better overall and disease-free survival as well as with LUMA hypomethylation. We conclude that global and gene-specific methylation patterns are independently associated with the clinical outcome in AML patients.

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Acknowledgements

This study was supported by the Swedish Cancer Foundation, Swedish Research Council and Stockholm County Council. MK was supported by a KI post doc grant.

A special thanks to Professor Per Guldberg in Copenhagen for his hospitality and help regarding methylation assay methodology.

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Author notes

  1. S Deneberg and M Grövdal: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden

    S Deneberg, M Grövdal, M Karimi, M Jansson, H Nahi, C Paul, E Hellström-Lindberg & S Lehmann

  2. Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    M Karimi & T J Ekström

  3. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    A Corbacioglu, V Gaidzik & K Döhner

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  1. S Deneberg
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Correspondence to S Deneberg.

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Authorship

Stefan Deneberg collected clinical data, analyzed data and wrote the article. Michael Grövdal performed the DGGE analyses and co-wrote the article. Mohsen Karimi performed the LUMA, MS-MCA and pyrosequencing. Monika Jansson performed DGGE analyses. Hareth Nahi helped collect clinical information. Andrea Corbacioglu, Verena Gaidzik and Konstanze Döhner performed the molecular analyses. Christer Paul co-wrote the article and supervised sample collection and storage. Tomas J Ekström performed the LUMA analysis and co-wrote the article. Eva Hellström-Lindberg helped design the study, assisted in data analysis and co-wrote the article. Sören Lehmann designed the study and co-wrote the article.

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Deneberg, S., Grövdal, M., Karimi, M. et al. Gene-specific and global methylation patterns predict outcome in patients with acute myeloid leukemia. Leukemia 24, 932–941 (2010). https://doi.org/10.1038/leu.2010.41

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