PRMT5 inhibition drives transcriptional reprogramming in MCL. In PDX-AA, spleens of mice treated in vivo for 2 weeks were harvested and human CD19⁺ cells were isolated and subjected to RNA sequencing. (A) Principal component analysis (PCA) of RNA sequencing data shows global differences in the transcriptome between treatment groups log tracks per million (TPM); SD > 0.9). Each dot represents and individual mouse. (B) Venn diagram depicting the number of down or up DEGs in mice treated with ibrutinib or PRT-382 in comparison to VC (q < 0.01; |log2FC| > 0.58). (C) Heatmap of the top 50 DEGs by q-value (q < 0.01; |log2FC| > 0.58). GSEA of PRT-382 in comparison with the VC, showing (D) key enrichment plots and (E) normalized enrichment scores (NES) of the top HALLMARK and REACTOME gene sets from Molecular Signatures Database (MsigDB). (F) GSEA of the top HALLMARK gene sets significantly enriched across 4 cell lines (Z-138, CCMCL1, SP53, and REC-1) treated with day 9 IC50 PRT-382 for 6 days in comparison with DMSO control.