Identification of two epitypes of IGHV unmutated chronic lymphocytic leukemia with distinct B-cell-related epigenetic imprinting and genetic alterations.

A transcription factor binding site analysis of both B‐cell‐related and independent differential CpGs did not reveal clear enrichments, with the exception of a highly significant association between the de novo hypomethylation signature of U‐CLLs C2 and the NFAT TF (Supporting Information S1: Figure 3L ), which has been commonly linked to epigenetic signatures in CLL. 4 , 5 , 12 Remarkably, when we analyzed B‐cell‐related differential CpGs, we noticed that the higher methylation levels in U‐CLL C1 resembled pre‐germinal center (GC) B cells, while methylation loss in U‐CLL C2 was shared with GC‐experienced B cells (Figure 2B ).

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