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Status |
Public on Feb 26, 2024 |
Title |
CHMP5-Mediated Transcriptional Regulation of T-Cell Acute Lymphoblastic Leukemia (Murine RNAseq) |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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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 |
CD45.2 Chmp5f/f CD4cre- (WT) or Chmp5f/f CD4cre+ (KO) bone marrow was transduced with ICN1-NGFR retrovirus and injected into lethally irradiated CD45.1 recipients. After 4 weeks and establishment of T-ALL disease, CD45.2+ NGFR+ cells from the spleen of recipient mice were isolated by FACS and submitted for RNAseq
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Contributor(s) |
Umphred-Wilson K, Adoro S, Ratnayake S, Chen Q |
Citation(s) |
38352301 |
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Submission date |
Sep 27, 2023 |
Last update date |
Feb 26, 2024 |
Contact name |
Stanley Adoro |
E-mail(s) |
stanley.adoro@nih.gov
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Organization name |
NCI
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Department |
CCR
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Lab |
EIB
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Street address |
Center Dr
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City |
Bethesda |
State/province |
MD |
ZIP/Postal code |
20892 |
Country |
USA |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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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 |
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Relations |
BioProject |
PRJNA1021646 |