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
  • 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. [email protected].
  • # 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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