title: 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.
abstract: In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-β and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Cahill
authors.forename: A-C
authors.initials: AC
authors.lastname: Bergh
authors.forename: M
authors.initials: M
authors.lastname: Kanduri
authors.forename: H
authors.initials: H
authors.lastname: Göransson-Kultima
authors.forename: L
authors.initials: L
authors.lastname: Mansouri
authors.forename: A
authors.initials: A
authors.lastname: Isaksson
authors.forename: F
authors.initials: F
authors.lastname: Ryan
authors.forename: K E
authors.initials: KE
authors.lastname: Smedby
authors.forename: G
authors.initials: G
authors.lastname: Juliusson
authors.forename: C
authors.initials: C
authors.lastname: Sundström
authors.forename: A
authors.initials: A
authors.lastname: Rosén
authors.forename: R
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000368:Aged; D001402:B-Lymphocytes / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D049109:Cell Proliferation; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region