Investigators hypothesized that heterogeneity in DNA methylation impacts leukemic evolution in CLL
They found higher proportions of discordant reads in CLL than either samples from normal B cells/diverse healthy human tissues
Presence of methylation ‘noise’ associated with reduced correlation between promoter methylation and gene silencing
Increase in discordant reads most prominent in genomic regions important to transcription
Significantly higher levels of discordant reads found in promoters of genes silenced in CLL, in differentially methylated regions and in genes important to pluripotency potential
Samples with increased disordered methylation had higher numbers of subclonal, but not clonal mutations
Unevolved CLLs largely unchanged epigenetic landscapes, while evolved CLLs demonstrated decreased methylation over time in promoters enriched for stem cell and MYC targets gene sets and increased methylation in TP53 targets
Increased heterogeneity found to be associated with shorter retreatment-free survival.
- Study data suggest heterogeneity in CLL DNA methylation results from random drift that subsequently undergoes positive selection and locally disordered DNA methylation.
View the original abstract on the ASH website.
