Recurrent mutations in enhancers (E) and super-enhancers (SE) contribute to lymphoma tumorigenesis, but their mutational landscape, targets, and functional impact in PTCL remain undefined.
Using CUT&RUN (H3K27ac and H3K27me3 marks) and RNA-seq, we mapped the epigenetic landscape of 29 PTCL cell lines and 7 PDX models, compared to normal T cell subsets (resting, activated, exhausted, and TFH) from 6 healthy donors. Our analysis revealed upregulated genes in the RHO GTPase cycle pathway and downregulated genes involved in protein lysine methyltransferases (PKMTs) function in PTCL compared to controls. These findings, along with other observed dysregulated pathways associated with chromatin organization and chromatin-modifying enzymes highlight a strong association between epigenetic dysregulation and PTCL pathogenesis.
Principal-component analysis of the transcriptomic and epigenetic landscape revealed subtype-specific gene regulation, highlighting distinct yet closely related features between AITL and TFH cells. Using Hi-C and RNA-seq, we investigated the 3D chromatin conformation in 17 diagnostic AITL patient samples. Genes within promoter-TFH-specific SE/E loops and stripes exhibited significantly higher expression compared to those in promoter-ENCODE enhancers outside TFH-associated loops and stripes (loops: p = 1.89 × 10⁻⁹¹, stripes: p = 8.22 × 10⁻²⁴). Based on the differential loop analysis using Peakachu, significant chromatin loops were observed in the MYC region and genes associated with pathways related to MYC, such as the Wnt signaling pathway and ErbB signaling pathway. AITL-specific loops in the MYC region were observed in eight of seventeen patients.
These findings underscore the role of tumor- and lineage-specific E/SE activity in modulating PTCL-specific gene expression patterns.
