title: Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.
abstract: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden. annamha@landspitali.is
authors.forename: Anna Margrét
authors.initials: AM
authors.lastname: Halldórsdóttir
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.forename: Millaray
authors.initials: M
authors.lastname: Marincevic
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Hanna
authors.initials: H
authors.lastname: Göransson
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.forename: Hans
authors.initials: H
authors.lastname: Ehrencrona
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018899:CpG Islands / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000235:genetics; D000077209:Decitabine; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005801:Genes, Homeobox; D005803:Genes, Immunoglobulin; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D014157:Transcription Factors; C012589:trichostatin A; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine