Transcriptomic profiling reveals differences in the modulation of gene expression after acute and chronic exposure of DLBCL subsets to HDACis. BCR-DLBCLs and OxPhos-DLBCLs were exposed to HDACis for 6 hours or 14 days before extraction of total RNA and RNA sequencing. (A) Top: the transcriptomes of OxPhos-DLBCLs were markedly less modulated by HDACi treatment than those of BCR-DLBCLs. Acute treatment produced similar numbers of up- and downregulated transcripts for each DLBCL subtype; chronic treatment resulted in a higher proportion of upregulated transcripts. Bottom: Venn diagrams show that for each DLBCL subtype, only a minor fraction of transcripts was commonly modulated at the 2 time points. Blue circles denote transcripts that are significantly modulated after 6 hours, yellow circles denote transcripts modulated after 14 days. Venn diagrams above the dashed line represent upregulated transcripts, and those below the line represent downregulated transcripts. (B) Top: gene set enrichment analysis (GSEA) showed that gene signatures for BCR-DLBCL and OxPhos-DLBCL molecular subtypes were significantly modulated in both DLBCL subsets by acute and chronic treatment with HDACis. Bottom: GSEA showed that processes required for the production of the antioxidant glutathione were modulated only in OxPhos-DLBCL treated with HDACi for 14 days (OxPhos 14 d). These processes were not modulated in OxPhos-DLBCLs and BCR-DLBCLs treated for 6 hours or in BCR-DLBCLs treated for 14 days (OxPhos 6 hrs, BCR 6 hrs, BCR 14 d, respectively). KEGG, Kyoto Encyclopedia of Genes and Genomes; NES, normalized enrichment score.