title: Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia.
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 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.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.forename: Nicola
authors.initials: N
authors.lastname: Cahill
authors.forename: Hanna
authors.initials: H
authors.lastname: Göransson
authors.forename: Camilla
authors.initials: C
authors.lastname: Enström
authors.forename: Fergus
authors.initials: F
authors.lastname: Ryan
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C541989:ABI3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D016328:NF-kappa B; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human