机构：[1]Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.[2]Immunology Training Program, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.[3]Computational Genomics and Bioinformatics Branch, Center for Biomedical Informatics & Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850.[4]College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.[5]Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030.
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.
基金：
This work was supported by grants from the US Department of Defense CA180768-W81XWH1910306 (S.A.); National Cancer Institute (NCI) K22 CA218467 (S.A.); National Institute of Allergy and Infectious Disease R01 AI1143992 (S.A.); American Cancer Society RSG-19-025-01-DDC (S.A.) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research ZIA BC 012135 (S.A.). L.Z. is supported by grants from the National Heart, Lung, and Blood Institute R01 HL103827 and NCI R01 CA222064. K.U-W. was supporte d in part by a Cell and Molecular Biology Training grant NIGMS T32 GM008056 to the Case Western Reserve University School of Medicine.
语种：
外文
PubmedID：
第一作者：
第一作者机构：[1]Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.[2]Immunology Training Program, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
通讯作者：
推荐引用方式(GB/T 7714)：
Umphred-Wilson Katharine,Ratnayake Shashikala,Tang Qianzi,et al.The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription[J].Biorxiv : The Preprint Server For Biology.2024,doi:10.1101/2024.01.29.577409.
APA：
Umphred-Wilson Katharine,Ratnayake Shashikala,Tang Qianzi,Wang Rui,Devaiah Ballachanda N...&Adoro Stanley.(2024).The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription.Biorxiv : The Preprint Server For Biology,,
MLA：
Umphred-Wilson Katharine,et al."The ESCRT protein CHMP5 promotes T cell leukemia by controlling BRD4-p300-dependent transcription".Biorxiv : The Preprint Server For Biology .(2024)
