Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia

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Blood, 14 January 2010, Vol. 115, No. 2, pp. 296-305.

Differential genome-wide array-based methylation profiles in prognostic subsets

of chronic lymphocytic leukemia

Meena Kanduri1,*, Nicola Cahill1,2,*, Hanna Göransson3, Camilla Enström4, Fergus

2, Anders Isaksson3, and Rosenquist1

1 Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden; 2

School of Biological Sciences, Dublin Institute of Technology (DIT), Dublin,

Ireland; 3 Department of Medical Sciences, Cancer Pharmacology and Informatic,

Uppsala University, Uppsala, Sweden; and 4 Department of Medical Sciences,

Molecular Medicine, Uppsala University, Uppsala, Sweden

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 microarrays

(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

(eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell

proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear

factor-B and mitogen-activated protein kinase pathways, respectively). In

contrast, these latter genes were silenced by methylation in IGHV mutated

patients. The array data were validated for selected genes using

methylation-specific polymerase chain reaction, quantitative reverse

transcriptase-polymerase chain reaction, and bisulfite sequencing. Finally, the

significance of DNA methylation in regulating gene promoters was shown by

reinducing 4 methylated tumor suppressor genes (eg, 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.

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