HDAC Inhibition Triggers Release of RNA Polymerase II from Promoter-Proximal Pausing in Healthy Blood Progenitors and...

Histone deacetylase (HDAC) inhibitors have been considered as anti-leukemic agents but have shown poor efficacy in clinical trials. In this study, we investigated the immediate transcriptional response to the HDAC inhibitor SAHA (vorinostat) in healthy CD34+ blood stem/progenitor cells and myeloblasts from patients with primary acute myeloid leukemia (AML) carrying TET2 and NPM1 mutations. We found that although healthy CD34+ and AML cells differed substantially at the transcriptional level, they responded very similarly to 10-minute SAHA treatment. HDAC inhibition led to a global increase in histone acetylation; however, only 150 to 250 genes were upregulated. These were involved in oxidative stress, metabolism, chromatin regulation, cell cycle control, and cell death, and the vast majority was upregulated in both healthy and AML cells. Upregulated genes were more highly acetylated compared with average expressed genes and had higher levels of promoter-proximal paused RNA polymerase II (Pol II) before treatment. Upon HDAC inhibition, upregulated genes increased BRD4 occupancy the most and released paused Pol II into transcription elongation. Our results suggest that the immediate effect of HDAC inhibition is to trigger release of paused Pol II into elongation. We speculate that the similar transcriptional response in healthy and leukemic cells may contribute to the poor efficacy of HDAC inhibitors in patients with hematologic malignancies.