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Genome-wide array-based methylation profiling reveals preferential methylation of homeobox transcription factor genes in mantle cell lymphoma and pro-apoptotic genes in chronic lymphocytic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Molecular Hematology)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are B-cell malignancies that differ with regards to biological and clinical characteristics. Aberrant DNA methylation has been described for each disorder, but comparison between the two entities is lacking. We employed high-resolution methylation microarrays (27,578 CpG sites) to compare methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 IGHV mutated, stereotyped subset #4 and 15 IGHV unmutated, stereotyped subset #1) samples. Distinct differences in methylation patterns were revealed between MCL and CLL, where MCL displayed a more homogenous profile. When comparing MCL and CLL/subsets, 51 genes were consistently identified as differentially methylated in all comparisons. Among 19 genes methylated in MCL, six were homeobox transcription factors (e.g. HLXB9, HOXA13), whereas unmethylated loci in MCL included genes enhancing proliferation and tumor progression (e.g. MERTK and CAMP). In contrast, apoptosis-related genes were prominent among genes methylated in CLL (e.g. DYRK2 and CYFIP2). Correlation between promoter methylation and gene expression was confirmed for selected genes using RQ-PCR. Notably, homeobox genes were not expressed in either entity, implying different gene silencing mechanisms in MCL and CLL. In summary, the differences in global methylation profiles between MCL and CLL have unfolded distinct epigenetic mechanisms operating in each disease.  

Keyword [en]
mantle cell lymphoma, chronic lymphocytic leukemia, Genome-wide array-based methylation profiling
URN: urn:nbn:se:uu:diva-132886OAI: oai:DiVA.org:uu-132886DiVA: diva2:359577
Available from: 2010-10-28 Created: 2010-10-28 Last updated: 2011-01-13
In thesis
1. Array-based Characterization of Chronic Lymphocytic Leukemia: - with Focus on Subsets Carrying Stereotyped B-cell Receptors
Open this publication in new window or tab >>Array-based Characterization of Chronic Lymphocytic Leukemia: - with Focus on Subsets Carrying Stereotyped B-cell Receptors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In chronic lymphocytic leukemia (CLL), the presence of multiple subsets expressing ‘stereotyped’ B-cell receptors (BCRs) has implicated antigen(s) in leukemogenesis. These stereotyped subsets display similar immunoglobulin (IG) gene usage, almost identical complementarity determining region 3’s and may share clinical features. For instance, subsets #1 (IGHV1/5/7/IGKV1-39) and #2 (IGHV3-21/IGLV3-21) have inferior outcome compared to non-subset patients, whereas subset #4 (IGHV4-34/IGKV2-30) display a favourable prognosis. The aim of this thesis was to investigate genomic aberrations, gene expression patterns and methylation profiles in stereotyped subsets and compare epigenetic profiles in CLL and mantle cell lymphoma (MCL).

In paper I, we investigated genomic aberrations in subsets #2, #4 and #16 and in non-stereotyped samples (n=101) using high-density 250K SNP arrays. Subset #2 and non-subset #2 IGHV3-21 cases displayed a higher frequency of aberrations than subset #4 cases. The high incidence of del(11q) in both subset #2/non-subset #2 may reflect the adverse survival reported for IGHV3-21 patients. In contrast, the lower frequency of genetic events and lack of poor-prognostic aberrations in subset #4 may partially explain their indolent disease. In paper II, we analysed the global RNA expression in subset #4, #16 and non-subset IGHV4-34 CLL patients (n=25). Subsets #4 and 16 showed distinct gene expression profiles, where genes involved in cell regulatory pathways were significantly lower expressed in subset #4, in line with their low-proliferative disease. In paper III, a genome-wide methylation array was applied to investigate methylation profiles in subsets #1, #2 and #4 (n=39). We identified differential methylation patterns for all subsets and found affected genes to be involved in e.g. apoptosis and therapy resistance. When performing functional annotation, a clear enrichment of genes involved in adaptive immunity was observed. These genes were preferentially methylated in subset #1 when compared to either subset #2 or #4, possibly due to different antigen responses. In paper IV, the genome-wide methylation profiles for 30 CLL and 20 MCL patients were investigated. Distinct methylation profiles were observed, where MCL displayed a more homogeneous profile. Homeobox transcription factor genes showed a higher degree of methylation in MCL, while apoptosis-related genes and proliferation-associated genes were methylated in CLL.

In summary, this thesis demonstrates that stereotyped CLL subsets display differences in gene expression profiles, genetic aberrations and methylation patterns, underscoring the functional relevance of subgrouping according to BCR stereotypy. The distinct methylation profiles of CLL and MCL suggests that different epigenetic mechanisms are involved in the pathogenesis of these B-cell malignancies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis Uppsala, 2010. 73 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 617
chronic lymphocytic leukemia, array-based characterization, stereotyped B-cell receptors, subsets, antigens, SNP array, gene expression array, methylation array
National Category
Medical Genetics
Research subject
Clinical Genetics
urn:nbn:se:uu:diva-132895 (URN)978-91-554-7936-7 (ISBN)
Public defence
2010-12-10, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Available from: 2010-11-18 Created: 2010-10-28 Last updated: 2011-01-13Bibliographically approved

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