Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict.

ABSTRACT: Bromodomain-containing protein 9 (BRD9) has emerged as a promising therapeutic target for blood cancers, including acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. PROTAC-based BRD9 degraders effectively hamper the growth and survival of leukemia cells; however, the underlying mechanism of these BRD9 degraders remains unclear. In this study, we demonstrated that depletion of BRD9 triggers DNA damage via R-loop accumulation, leading to conflicts between transcription and replication processes. Replication stress inhibits the proliferation of leukemia cells and promotes their differentiation. Mechanistically, BRD9 plays a pivotal role in recruiting BRD2 and BRD4 to chromatin through direct interactions, which is critical for preventing R-loop formation during trans

SUBMITTER: Lee SY 

PROVIDER: S-EPMC12231585 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature