2. Academic Validation
  3. The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription

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

  • Nat Commun. 2025 May 3;16(1):4133. doi: 10.1038/s41467-025-59504-9.
Katharine Umphred-Wilson 1 2,  Shashikala Ratnayake # 3,  Qianzi Tang # 4,  Rui Wang # 4,  Sneha Ghosh Chaudhary 1,  Devaiah N Ballachanda 1,  Josephine Trichka 1 2,  Jan Wisniewski 1,  Lan Zhou 5,  Qingrong Chen 3,  Daoud Meerzaman 3,  Dinah S Singer 1,  Stanley Adoro 6
Affiliations

Affiliations

  • 1 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 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, USA.
  • 4 College of Animal Science and Technology, Sichuan Agricultural University, 611130, Chengdu, China.
  • 5 Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • 6 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. stanley.adoro@nih.gov.
  • # Contributed equally.
PMID: 40319015 DOI: 10.1038/s41467-025-59504-9
Abstract

Addiction to oncogene-rewired transcriptional networks is a therapeutic vulnerability in Cancer cells, underscoring a need to better understand mechanisms that relay oncogene signals to the transcriptional machinery. Here, using human and mouse T cell acute lymphoblastic leukemia (T-ALL) models, we identify an essential requirement for the endosomal sorting complex required for transport protein CHMP5 in T-ALL epigenetic and transcriptional programming. CHMP5 is highly expressed in T-ALL cells where it mediates recruitment of the coactivator BRD4 and the histone acetyl transferase p300 to enhancers and super-enhancers that enable transcription of T-ALL genes. Consequently, CHMP5 depletion causes severe downregulation of critical T-ALL genes, mitigates chemoresistance and impairs T-ALL initiation by oncogenic NOTCH1 in vivo. Altogether, our findings uncover a non-oncogene dependency on CHMP5 that enables T-ALL initiation and maintenance.

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