DNA methylation analysis indicates that CLL arises from a continuum of B-cell development states.
Major finding: DNA methylation analysis indicates that CLL arises from a continuum of B-cell development states.
Concept: Most previously identified CLL methylation events are associated with normal B-cell development.
Impact: DNA methylation patterns indicating increased maturation were associated with improved clinical outcome.
In chronic lymphocytic leukemia (CLL), distinct DNA methylation subtypes have been identified, but distinguishing cancer-specific epigenetic alterations from the epigenetic marks of normal B-cell development has proven difficult. Oakes and colleagues used whole-genome bisulfite sequencing to identify DNA methylation signatures in normal B cells during maturation. Methylation loss occurred as maturity increased in normal B cells, with hypomethylation at enhancer and promoter regions, and hypermethylation at regions of transcriptional elongation, indicating that methylation status is essential in B-cell maturation and function. Chromatin immunoprecipitation sequencing indicated that the hypomethylated regions were enriched for binding of several transcription factors. Unsupervised clustering of the methylation data from patients with CLL separated CLL into three subtypes: low-programmed (LP-CLL), intermediate-programmed (IP-CLL), and high-programmed (HP-CLL). HP-CLL had increased methylation of CpGs in transcriptional elongation regions, and LP-CLL had reduced methylation of several transcription factor binding sites. Clinically, increased methylation was associated with improved survival, with HP-CLL having the best survival rate. Methylation patterns in CLL were compared to methylation in normal B cells. When the changes in CLL corresponded to normal B cells, this was coined “successful methylation programming.” Many genes previously reported to be hypermethylated in CLL were also hypermethylated in normal B-cell development. However, a number of abnormal methylation events also occurred, including failed methylation of sites methylated during normal B-cell maturation, and aberrant methylation of sites not normally methylated in B cells. Together, these findings suggest that DNA methylation patterns distinct from normal B-cell maturation contribute to CLL development.
Oakes CC, Seifert M, Assenov Y, Gu L, Przekopowitz M, Ruppert AS, et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 2015 Jan 18 [Epub ahead of print].
- ©2016 American Association for Cancer Research.