Epigenetic signature reveals the hierarchical programming of CLL T cells toward terminal differentiation and metabolic imbalance. (A) Principal component (PC) analysis of chromatin-accessibility profiles for WT, intermediate (interm)-stage, and late-stage AT Eμ-TCL1 CD8⁺ T cells using ATAC sequencing (ATAC-seq). (B) Venn diagram of overlap in the number of significantly more open (red; top) or more closed (blue; bottom) chromatin regions in interm- and late-stage AT Eμ-TCL1 CD8⁺ T cells relative to WT cells. (C) Peak annotation pie chart showing the genomic location of ATAC-seq peaks in CD8⁺ T cells. (D) Heat map of significantly changed ACRs in interm- and late-stage Eμ-TCL1 CD8⁺ T cells relative to WT cells. Numbers beside gene symbols indicate distance to transcription start site, and boxes highlight selected genes related to T-cell exhaustion, memory, and metabolic activity. (E) ATAC-seq tracks for selected genes (Havcr2, Tcf7, Vdac1, Timm8a2, Insr, and Pfkp). Significantly different ACR peaks in interm- and/or late-stage Eμ-TCL1 CD8⁺ T cells relative to WT control are highlighted. (F) Heat map from our previously published data set showing significantly changed ACRs in OT-I CD8⁺ T cells isolated from AT Eμ-TCL1 and WT mice 7 days after infection with murine cytomegalovirus-ovalbumin–expressing SINFEKL peptide. Arrows pointing to relevant genes related to either T-cell exhaustion (red) or memory differentiation and metabolic activity (light blue). Significance was calculated as false discovery rate adjusted P value < .05 in panels A-F.