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Chronic Lymphocytic Leukemia

450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments

Leukemia volume 27, pages 150–158 (2013)Cite this article

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Abstract

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-β and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.

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Acknowledgements

This research was supported by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council, and the Lion’s Cancer Research Foundation, Uppsala. Methylation profiling was performed by the SNP&SEQ Technology Platform in Uppsala, which is supported by Uppsala University, Uppsala University Hospital, Science for Life Laboratory—Uppsala and the Swedish Research Council (Contracts 80576801 and 70374401).

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    N Cahill, M Kanduri, L Mansouri, C Sundström & R Rosenquist

  2. Department of Biological Sciences, Institute of Technology, Dublin, Ireland

    N Cahill & F Ryan

  3. Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping, Sweden

    A-C Bergh & A Rosén

  4. Department of Clinical Genetics and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg, Sweden

    M Kanduri & A Isaksson

  5. Department of Medical Sciences, Cancer Pharmacology and Informatics, Uppsala University, Uppsala, Sweden

    H Göransson-Kultima

  6. Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

    K E Smedby

  7. Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden

    G Juliusson

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Cahill, N., Bergh, AC., Kanduri, M. et al. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. Leukemia 27, 150–158 (2013). https://doi.org/10.1038/leu.2012.245

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