Page 48 - 2021_04-Haematologica-web

T. Lewis et al.
gy, JJN3 and primary CLL cells (n=5) were treated with increasing concentrations of DC-1-192 both alone and in combination with bortezomib in JJN3 cells and ibrutinib in CLL samples. The fixed molar ratios employed in the combination studies were determined experimentally
using the LD50 values calculated from the previous toxicity data. The fraction affected plots and isobologram plots for the drugs and drug combinations in JJN3 cells (Figure 6A), and in primary CLL cells (Figure 6B) show that the cytotoxic effects of DC-1-192 are potentiated by the
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Figure 5. RNA sequencing and gene set enrichment analysis revealed that DC-1-170 and DC-1-192 preferentially inhibited NF-κB target genes. (A) Unsupervised hierarchical clustering revealed a strong drug-associated transcriptional signature for both DC-1-170 and DC-1-192. (B) The majority 4,418/5,077 (87%) of the sig- nificantly altered transcripts were downregulated in response to drug. Strikingly, 4,040/5,077 (80%) of the changes were common to both DC-1-170 and DC-1-192. (C) Gene set enrichment analysis showed over-representation of NF-κB target genes in the gene list commonly downregulated by exposure to DC-1-170 and DC-1- 192. (D) The top 12 over-represented pathways in the commonly downregulated gene list following exposure to DC-1-170 and DC-1-192 are shown. The table also shows the normalized enrichment scores, P values and false discovery rates (FDR) for each canonical gene set.
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haematologica | 2021; 106(4)