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| Status |
Public on Feb 26, 2024 |
| Title |
CHMP5-Mediated Transcriptional Regulation of T-Cell Acute Lymphoblastic Leukemia (Human RNAseq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Oncogene activity rewires cellular transcription to create new transcriptional networks which cancer cells become addicted to through mechanisms that remain unresolved. Using human and mouse models of T-cell acute lymphoblastic leukemia (T-ALL), we identified an essential requirement of the endosomal sorting complex required for transport (ESCRT) protein CHMP5 in enabling the T-ALL transcriptional program. Loss of CHMP5 impaired recruitment of the bromodomain transcriptional coactivator BRD4 to enhancer and super-enhancers which caused RNA polymerase II stalling, resulting in severe downregulation of key pro-leukemogenic genes, including MYC and MYC-target genes. Mechanistically, CHMP5 facilitated BRD4 interaction with the histone acetyl transferase p300 to promote H3K27 acetylation at pro-T-ALL gene regulatory elements. Validating its importance to T-cell leukemogenesis, CHMP5-deficiency mitigated chemoresistance in human T-ALL cells and abrogated T-ALL initiation by oncogenic NOTCH1 in vivo. Collectively, our results uncover an unexpected transcriptional activity of CHMP5 that is essential for T-ALL pathogenesis.
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| Overall design |
RNAseq of CUTLL1 cells treated with control shRNA (CT) and CHMP5 shRNA (KD).
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| Contributor(s) |
Umphred-Wilson K, Adoro S, Ratnayake S, Chen Q |
| Citation(s) |
38352301 |
| |
| Submission date |
Sep 27, 2023 |
| Last update date |
Feb 26, 2024 |
| Contact name |
Stanley Adoro |
| E-mail(s) |
stanley.adoro@nih.gov
|
| Organization name |
NCI
|
| Department |
CCR
|
| Lab |
EIB
|
| Street address |
Center Dr
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
| |
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| Platforms (1) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE244200 |
CHMP5-Mediated Transcriptional Regulation of T-Cell Acute Lymphoblastic Leukemia |
|
| Relations |
| BioProject |
PRJNA1021644 |
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