The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription

Abstract

SummaryOncogene activity rewires cellular transcription, creating new transcription networks to which cancer cells become addicted, by mechanisms that are still poorly understood. Using human and mouse models of T cell acute lymphoblastic leukemia (T-ALL), we identify an essential nuclear role for CHMP5, a cytoplasmic endosomal sorting complex required for transport (ESCRT) protein, in establishing and maintaining the T-ALL transcriptional program. Nuclear CHMP5 promoted the T-ALL gene program by augmenting recruitment of the co-activator BRD4 by the histone acetyl transferase p300 selectively at enhancers and super-enhancers, an interaction that potentiated H3K27 acetylation at these regulatory enhancers. Consequently, loss of CHMP5 diminished BRD4 occupancy at enhancers and super-enhancers and impaired RNA polymerase II pause release, which resulted in downregulation of key T-ALL genes, notablyMYC. Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1in vivo. Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease.Graphical abstractHighlightsIdentification of a nuclear role for the cytosolic ESCRT protein CHMP5 in transcriptionCHMP5 mediates BRD4-dependent Pol II pause release and transcription of T-ALL genesP300-BRD4 induced enhancer and super-enhancer H3K27 acetylation requires CHMP5CHMP5 depletion mitigates chemoresistance and abrogates T-ALL initiationin vivo