Altered epigenetic modifications lead to cancer evolution and progression. Pastore and colleagues integrated DNA methylation (DNAme), histone modification, and RNA-seq data in 22 primary chronic lymphocytic leukemia (CLL) and 13 healthy donor B lymphocyte samples. CLL differed from normal B cells at 297 differentially regulated super-enhancers (SE) and 41057 differentially methylated regions. CLL-specific SEs were hypomethylated in proximity to BCL2, LEF1, and CTLA4, genes involved in lymphocyte proliferation and differentiation. Further integration of single-cell DNAme data verified the corrupted coherence of epigenetic modifications and decreased mutual information in epigenetic-transcriptional coordination in CLL, suggesting cell-to-cell heterogeneity. Moreover, mutually exclusive activating and repressing histone marks colocalized in corrupted chromatin states, indicating intratumoral heterogeneity. Data mining at corrupted regions revealed dysregulation of transcription by polycomb-mediated repression of MYC targets, indicative of CLL evolution.

Expert Commentary: This work offers mechanistic insights into the intratumoral epigenetic variability of CLL and its transcriptional diversity....

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