The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription.
The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription.
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ESCRT 蛋白 CHMP5 通过控制 BRD4-p300 依赖性转录促进 T 细胞白血病。
DOI：
10.1101/2024.01.29.577409
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Adoro,Stanley
中科院分区：
文献类型：
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作者：
Umphred-Wilson,Katharine;Ratnayake,Shashikala;Tang,Qianzi;Wang,Rui;Devaiah,BallachandaN;Zhou,Lan;Chen,Qingrong;Meerzaman,Daoud;Singer,DinahS;Adoro,Stanley
Oncogene 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, notably MYC. Reinforcing its importance in T-ALL pathogenesis, CHMP5 deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL induction by oncogenic NOTCH1 in vivo. Thus, the ESCRT protein CHMP5 is an essential positive regulator of the transcriptional machinery promoting T-ALL disease.
