CDK9 Inhibition with enitociclib reveals influence on HERV and LINE RNA abundances in whole blood, T-, and B-Cell lines

Abstract Endogenous retroelements (EREs) comprise a significant portion of the human genome and there is a growing appreciation for their roles in eukaryotic physiology. In lymphomas, EREs may contribute to proto-oncogene expression and their RNA expression can be useful to better define lymphoma sub-classifications. Several emerging cancer therapies suggest that targeting ERE expression may even be beneficial to patient outcome. In this study, we investigated how enitociclib, a CDK9 inhibitor, impacted ERE expression over time. Using in vitro models of T and B lymphocytes, we found that CDK9 inhibition upregulates transcriptional abundances of ERE RNAs in a cell type- and temporal- specific manner. Leveraging this data with data collected from a retrospective cohort of patients with lymphomas receiving enitociclib, we found that ERE activity was initially downregulated, followed by a substantial upregulation in expression before a return to baseline expression levels within forty-eight hours. These results showed that ERE activity is differentially sensitive to CDK9 inhibition and highlights the complexity of interactions between the P-TEFb complex and nascent ERE RNAs.