Page 117 - Haematologica May 2022

CDK12-transcription reprogramming in MCL and DLBCL
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Figure 4. MDR1 upregulation drives resistance to THZ531 in mantle cell lymphoma and other aggressive B-cell lymphomas. (A) Dose-response curves of Z138, Jeko-1 and REC-1 cell lines after 72 h of treatment with THZ531. Data are shown as mean ± standard deviation (SD) of three technical replicates for each cell line. (B) Western blot analysis of phosphorylation of RNAPII in Ser2, 5 and 7, RNAPII, cleaved PARP, phosphor-p70S6K, p70S6K, phosphor-4EBP1, 4EBP1, MCL-1, BCL- XL, BCL-2 and MYC protein expression in REC-1 cells treated with the indicated doses of THZ531 at different time points. (C) Volcano plot showing no changes at the mRNA level after THZ531 treatment for 24 h relative to treatment with dimethylsulfoxide (DMSO) in REC-1 cells. Red: upregulated genes, black: downregulated genes. LFC: log2 fold change cutoff of log2 (1.5), P-value cutoff of 0.05. Three biologically independent samples. (D) Bar plot of differential expression of drug pump genes in the THZ531-resistant cell line REC-1 versus the THZ531-sensitive cell lines Z138 and Jeko-1. Bar length represents log2 fold change. Color represents direction of expressions change where red represents genes with log2 fold change greater than 1.5 and blue represents genes with log2 fold change less than 1.5. (E) Dose- response curves of REC-1 cells after 72 h of treatment with different doses of THZ531, tariquidar, or THZ531+tarquidar. Data are shown as mean ± SD of three tech- nical replicates for each cell line. (F) Dose-response curves of the KARPAS-422-THZ-R and Maver-1-THZ-R cell lines after 72 h of treatment with different doses of THZ531, tariquidar, or THZ531+tariquidar. Data are shown as mean ± SD of three technical replicates for each cell line. Data shown in (A, E and F) are representative of at least three independent experiments.
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