Pharmacodynamic and molecular changes associated with CC-486 treatment. (A) Tumor methylation changes (CpGs with >10% of differential methylation and Q value <0.05) upon CC-486 administration by chromosome location in 5 tumors. Hypomethylated and hypermethylated regions are labeled as blue and red, respectively. (B) Changes in cell-free DNA (cfDNA) hydroxymethylation (H-MET) (left) and methylation (MET) (right) as percentage over total cfDNA in 22 patients comparing cycle 1, day −6 (C1 D-6) versus cycle 1, day 1 (C1 D1). (C) Volcano plot of tumor transcriptional changes by RNA-sequencing of 5 lymphoma paired samples. Upregulated genes associated with immune pathways are depicted in dark blue. (D) Gene Set Enrichment Analysis (GSEA) of significantly upregulated genes from panel C (interferon-α, interferon-β, interferon-γ). (E) Interferon-λ/IL-29 concentration in 14 paired plasma samples. (F) Tumor methylation changes (CpGs with >10% of differential methylation and Q value <0.05) upon CC-486 administration by chromosome location in CD3+ T cells from 3 patients. (G) Pathway analysis of differentially methylated gene promoters from CD3+ T cells, including genes associated with “lymphocyte activation” and “regulation of immune system progress” pathways. *Lymphocyte activation related genes are ADAM8, C17orf99, CD79B, DLG5, DUSP10, FOXP1, HDAC4, HLA-DPA1, ICOS, MYH9, PKN1, RIPK3, SLA2, SOX13, and TNFRSF13B. †Regulation of immune system process related genes are ADAM8, ADORA2B, ATXN1L, BP1FB1, C17orf99, CIR, CD79B, COCH, COL2A1, DLG5, DUSP10, FCN3, FOXP1, HLA-DPA1, ICOS, LY96, MIR140, ORM2, PILRB, PKN1, RIPK3, SLA2, SOX13, TNFRSF13B, and YTHDF2.