The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription
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.
Authors
- Katharine Umphred-Wilson (ORCID: https://orcid.org/0000-0001-6416-0466)
- Shashikala Ratnayake
- Lan Zhou (ORCID: https://orcid.org/0000-0002-9883-135X)
- Josephine Trichka (ORCID: https://orcid.org/0000-0002-1997-3502)
- Daoud Meerzaman (ORCID: https://orcid.org/0000-0002-0129-5256)
- Devaiah N Ballachanda
- Dinah S. Singer (ORCID: https://orcid.org/0000-0002-7369-3018)
- Stanley Adoro (ORCID: https://orcid.org/0000-0001-9092-5960)
- Sneha Ghosh Chaudhary (ORCID: https://orcid.org/0009-0004-4031-9152)
- Jan Wiśniewski (ORCID: https://orcid.org/0000-0002-9131-0711)
- Qianzi Tang (ORCID: https://orcid.org/0000-0003-3235-3372)
- Rui Wang (ORCID: https://orcid.org/0000-0002-6842-119X)
- Qingrong Chen (ORCID: https://orcid.org/0000-0003-1325-6147)
Institutions
- National Institutes of Health (US)
- Sichuan Agricultural University (CN)
- Methodist Hospital (US)
- National Cancer Institute (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1038/s41467-025-59504-9
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- U.S. Department of Defense
- American Cancer Society
- Case Western Reserve University
- School of Medicine, Case Western Reserve University
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases