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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.
Meena Kanduri,*, Nicola Cahill,*, Hanna Göransson, Camilla Enström4, Fergus Ryan, Anders Isaksson, and Richard Rosenquist. Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia. Blood, 14 January 2010, Vol. 115, No. 2, pp. 296-305. Blood. © the American Society of Hematology." doi:10.1182/blood-2009-07-232868