Transcriptional Condensates: Epigenetic Reprogramming and Therapeutic Targets in Hematologic Malignancies

Transcription is a core hallmark of cancer, wherein many different proteins assemble at specific sites in the nucleus and act in concert to transcribe functionally relevant genes. Central to this process are transcription factors that bind to their cognate DNA motifs on enhancers and super-enhancers to recruit cofactors, coactivators, and epigenetic modifiers, thereby inducing or repressing gene expression. Super-enhancers drive oncogenic transcription, to which cancer cells become highly addicted and confer tumor dependencies on super-enhancer-driven transcription machinery. Transcriptional condensates (TCs) are nuclear membrane-less assemblies of DNA-binding transcription factors, transcription co-activators, and the transcriptional machinery (such as RNA polymerases, non-coding RNAs) formed through liquid-liquid phase separation (LLPS). The function of transcriptionally active oncogenic proteins and their interplay with nucleic acids are carried out within these biomolecular condensates, allowing them to spatiotemporally regulate oncogene expression and lead to the induction and maintenance of cancer. With this growing understanding, specific inhibitors and strategies targeting TC assembly and activation should be considered promising therapeutic opportunities for treating various tumors, including hematological malignancies.