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Chronic lymphocytic leukemia subsets with stereotyped B cell receptors are distinguished by unique methylation patterns
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Molecular Hematology Richard Rosenquist)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Epigenetic modifications, such as DNA methylation, are crucial for both normal and tumor cell development. In chronic lymphocytic leukemia (CLL), multiple subsets have been reported that carry closely homologous, “stereotyped” B cell receptors (BCRs) with varying clinical outcome. To compare the methylation profiles of stereotyped CLL subsets, we here applied high-resolution methylation arrays (27,578 CpG sites) to 3 major subsets, i.e. poor-prognostic subsets #1 (IGHV1/5/7/IGKV1-39/1D-39, n=15) and #2 (IGHV3-21/IGLV3-21, n=9) and favorable-prognostic subset #4 (IGHV4-34/IGKV2-30, n=15). Overall, our results demonstrated significantly different and unique methylation profiles between these stereotyped subsets. Of particular interest was the observation that genes involved in apoptosis (e.g. RIPK3, AATK and TCF3) were methylated in subset #1 compared to subset #4, whilst genes involved in therapy resistance (e.g. ABCB11 and ITGAM) were unmethylated in subset #2 when compared to subset #4. Functional annotation of the differentially methylated genes revealed marked differences in genes involved in the adaptive immune response (e.g. CD80 and CD86), which generally remained unmethylated in subsets #2 and #4 in contrast to subset #1, indicating potential differences in antigenic response between subsets. Taken together, this data convincingly illustrates the distinct methylation profiles amongst stereotyped CLL cases and highlights a key role for epigenetics in disease pathogenesis.

Keyword [en]
Chronic lymphocytic leukemia
Research subject
Clinical Genetics
URN: urn:nbn:se:uu:diva-132884OAI: oai:DiVA.org:uu-132884DiVA: diva2:359578
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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