liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
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
Uppsala University, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Uppsala University, Sweden.
Uppsala University, Sweden.
Show others and affiliations
2013 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, 150-158 p.Article in journal (Refereed) Published
Abstract [en]

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, analysing 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 (e.g. CLLU1, LPL, ZAP70, NOTCH1), epigenetic regulator (e.g. HDAC9, HDAC4, DNMT3B), B-cell signaling (e.g. IBTK) and numerous TGF-ß 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.Leukemia accepted article preview online, 27 August 2012; doi:10.1038/leu.2012.245.

Place, publisher, year, edition, pages
2013. Vol. 27, no 1, 150-158 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-80705DOI: 10.1038/leu.2012.245ISI: 000313511400021PubMedID: 22922567OAI: diva2:547813
Available from: 2012-08-29 Created: 2012-08-29 Last updated: 2016-02-04
In thesis
1. Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
Open this publication in new window or tab >>Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.

In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.

In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.

Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.

The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.

This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 83 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1501
National Category
Cell and Molecular Biology Clinical Medicine
urn:nbn:se:liu:diva-124576 (URN)10.3384/diss.diva-124576 (DOI)978-91-7685-867-7 (Print) (ISBN)
Public defence
2016-02-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-02-04Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Bergh, Ann-CharlotteRosén, Anders
By organisation
Cell BiologyFaculty of Health Sciences
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 87 hits
ReferencesLink to record
Permanent link

Direct link