mRNA gene expression profiling in a human AML cell line treated with small molecule inhibitors that impact different RNA polymerase transcription complexes, or their combination, in comparison to a global DNA-damaging anthracycline compound

Our results confirmed that CX-5461, a Pol I inhibitor, does not significantly impact mRNA expression at 6 hrs, while I-BET151 alone, known to inhibit MYC and expression of other oncognes, resulted in widespread changes in select gene expression programs as previously demonstrated (Dawson et al., 2011). Interestingly, the combination of CX-5461 and I-BET151 demonstrated no further gene expression changes from I-BET151 alone, suggesting that their mechanism of synergy is more likely directly associated with the CX-5461-mediated DNA damage response. Further, the mRNA gene expression changes following drug combination treatment are distinct from those following doxorubicin treatment, supporting that the synergistic effects of the novel combination of CX-5461 and I-BET151 do not rely on global DNA damage. Comparative gene expression profiling of the acute myeloid leukemia (AML) MV4-11 cells treated with the novel small molecule inhibitor CX-5461 (Pol I-mediated transcription inhibitor) or I-BET151 (BET protein inhibitor) or their combination, in comparison to treatment with the DNA damaging anthracycline doxorubicin. We use 3' gene expression profiling to characterise transcriptional programs associated with acute response (6 hour) to treatment with the single agents CX-5461 and I-BET151, representing inhibitors of Pol I and Pol II transcription, respectively, or their combination in the p53 wt MV4-11 acute myeloid leukaemia (AML) cell line. This was in comparison to 2 hr treatment with IC90 doxorubicin, a DNA damaging agent representing the anthracycline class of drug used in standard AML treatment.