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

Katharine Umphred-Wilson, Shashikala Ratnayake, Qianzi Tang, Rui Wang, Sneha Ghosh Chaudhary, Devaiah N. Ballachanda, Josephine Trichka, Jan Wisniewski, Lan Zhou, Qingrong Chen, Daoud Meerzaman, Dinah S. Singer and Stanley Adoro ()
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Katharine Umphred-Wilson: National Institutes of Health
Shashikala Ratnayake: National Institutes of Health
Qianzi Tang: Sichuan Agricultural University
Rui Wang: Sichuan Agricultural University
Sneha Ghosh Chaudhary: National Institutes of Health
Devaiah N. Ballachanda: National Institutes of Health
Josephine Trichka: National Institutes of Health
Jan Wisniewski: National Institutes of Health
Lan Zhou: Houston Methodist Hospital
Qingrong Chen: National Institutes of Health
Daoud Meerzaman: National Institutes of Health
Dinah S. Singer: National Institutes of Health
Stanley Adoro: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59504-9

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