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

Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Blood (Impact Factor: 10.45). 11/2009; 115(2):296-305. DOI: 10.1182/blood-2009-07-232868
Source: PubMed


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-kappaB 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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    • "In addition, recent studies implicate that particular epigenetic regulations of some genes, including VHL gene, may play a crucial role in other hematological and non-hematological malignancies. Namely, it was demonstrated that epigenetic changes were found to be involved in pathogenesis of chronic lymphocytic leukemia [29] and endometrial cancer [30]. Moreover, these findings may have an important clinical implication in the era of hypomethylating therapy. "
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    • "Hypermethylated tumor suppressor genes (ABI3, SCGB2A1, VHL, GPX3, IGSF4 and SERPIND5) were identified in unmutated CLL. In mutated cases, hypermethylation genes were involved in cell proliferation and NF-κB pathway (ADORA3, AIRE, CARD15, LOC340061, UNC5CL and LDOC1) and MAPK pathway (PRF1, FABP7) [15]. "
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