Large-Scale Analysis of DNA Methylation In Chronic Lymphocytic Leukemia

Abstract

Aims: B-cell chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy that clinically ranges from indolent to rapidly progressive. CLL, like other cancers, can be affected by epigenetic alterations. Materials & methods: A microarray discovery-based study was initiated to determine DNA methylation in CLL cases with a range of CD38 expression (1–92%). Results: Many loci were either methylated or unmethylated across all CD38 levels, but differential methylation was also observed for some genes. Genomic sequencing of DLEU7 confirmed extensive cytosine methylation preferentially in patient samples with low CD38 expression, whereas NRP2, SFRP2 and ADAM12 were more commonly methylated in those with high CD38 expression. Conclusion: This study demonstrates that CLL is affected by CpG island methylation in some genes that segregate with CD38 expression levels, while most others show similar methylation patterns across all levels. The CpG island methylation in certain functional gene groups and pathway-associated genes that are known to be deregulated in CLL provides additional insights into the CLL methylome and epigenetic contribution to cellular dysfunction. It will now be useful to investigate the effectiveness of epigenetic therapeutic reversal of these alterations to develop effective treatments for the disease.

KEYWORDS::

• CD38 expression
• CLL
• DNA methylation
• epigenetics
• leukemia

Acknowledgements

We thank Susan Souchek, Laura Jacobus, Melinda Andreski and Kathy Olson for assistance with tissue banking and Angel Surdin for expert editorial assistance.

Financial & competing interests disclosure

Support was provided from the National Cancer Institute grants CA 100055 and CA097880 (CWC), CA123018 (HS), CA113408 (TS) and the CRC Missouri Chair in Cancer Research (CWC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Support was provided from the National Cancer Institute grants CA 100055 and CA097880 (CWC), CA123018 (HS), CA113408 (TS) and the CRC Missouri Chair in Cancer Research (CWC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.