Epigenetic Heterogeneity in Non-Hodgkin Lymphoma

In chronic lymphocytic leukemia (CLL) genetically distinct subpopulations are commonly observed and predict future evolutionary and clinical trajectories. Similar to the case of intra-tumoral genetic diversity, intra-tumoral epigenetic diversity occurs at the level of DNA methylation, leading to massive stochastic diversification in methylation patterns. Importantly, stochastic "epimutations" impact transcription, clonal evolution and clinical outcome.

To robustly differentiate "epidrivers" from the majority of random passenger DNA methylation changes, a novel statistical inference framework has been developed that accounts for the varying epimutation rate across the genome. This framework can also include histone modifications revealing a decrease in the coherence between different epigenetic marks in CLL and consistent with intra-leukemic epigenetic diversity. Finally, multi-omic single-cell sequencing techniques further allow for tracking of epimutations and inferring high-resolution lineage trees.