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Blood First Edition Paper, prepublished online November 6, 2009; DOI 10.1182/blood-2009-07-232868. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Kanduri, M. Articles by Rosenquist, R. PubMed PubMed Citation Articles by Kanduri, M. Articles by Rosenquist, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 13, 2009; accepted October 10, 2009. Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia Meena Kanduri1, Nicola Cahill1, Hanna Goransson2, Camilla Enstrom3, Fergus Ryan4, Anders Isaksson2 and Richard Rosenquist1,3 1 Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden; 2 Department of Medical Sciences, Cancer Pharmacology and Informatic, Uppsala University, Uppsala, Sweden; 3 Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden; 4 School of Biological Sciences, Dublin Institute of Technology (DIT), Dublin, Ireland * Corresponding author; email: richard.rosenquist{at}genpat.uu.se Abstract Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer, however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here we analyzed the global methylation profiles in CLL, by applying high-resolution methylation micro-arrays (27,578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (e.g. VHL, ABI3 and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (e.g. ADORA3 and PRF1 enhancing the NF-B and MAPKinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data was validated for selected genes using methylation-specific PCR, quantitative RT-PCR and bi-sulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by re-inducing 4 methylated tumor suppressor genes (e.g. VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2'-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020