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Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

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


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.



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