Cyclin-dependent kinase 9 (CDK9) inhibition represents a promising therapeutic strategy in cancers that disrupts RNA polymerase II pause release and collapses oncogenic transcripts. Here, we show that CDK9 inhibition also induces widespread transposable element (TE) activation across diverse cancer types. In acute myeloid leukemia (AML), CDK9 inhibition induces rapid epigenetic reprogramming and robust TE upregulation. To dissect this non-canonical transcriptional response, we developed TEgment, a TE-centric RNA-sequencing analysis pipeline that classifies TE expression into distinct structural modalities: standalone, readthrough, protein-coding gene-embedded (5'UTR, coding exons, and 3'UTRs), lncRNA-embedded, intron-retained, and TE-initiated/terminated transcription events. Applying TEgment to CDK9-inhibited AML revealed that TEs are predominantly expressed as readthrough, 3'UTR-embedded, and lncRNA-embedded transcripts rather than autonomous units, challenging prevailing assumptions about TE reactivation. TEgment provides a versatile framework for resolving TE transcriptional modalities at locus and structural levels, enabling precise interpretation of TE-derived transcripts in cancer and other contexts.
Prokopov, D., Moussa, A., Tunbak, H., Leddy, E., Deniz, O.
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