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; Stanley Adoro

doi:10.1038/s41467-025-59504-9

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, Stanley Adoro

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	4133
Pages (from-to)	4133
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59504-9
State	Published - Dec 2025

Keywords

Humans
Animals
Transcription Factors/metabolism
Cell Cycle Proteins/metabolism
Mice
Endosomal Sorting Complexes Required for Transport/metabolism
Transcription, Genetic
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
Cell Line, Tumor
Gene Expression Regulation, Leukemic
Receptor, Notch1/metabolism
E1A-Associated p300 Protein/metabolism
Leukemia, T-Cell/genetics
p300-CBP Transcription Factors/metabolism
Bromodomain Containing Proteins
Nuclear Proteins

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-025-59504-9

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Umphred-Wilson, K., Ratnayake, S., Tang, Q., Wang, R., Chaudhary, S. G., Ballachanda, D. N., Trichka, J., Wisniewski, J., Zhou, L., Chen, Q., Meerzaman, D., Singer, D. S., & Adoro, S. (2025). The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription. Nature Communications, 16(1), 4133. Article 4133. https://doi.org/10.1038/s41467-025-59504-9

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title = "The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription",

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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author = "Katharine Umphred-Wilson and Shashikala Ratnayake and Qianzi Tang and Rui Wang and Chaudhary, \{Sneha Ghosh\} and Ballachanda, \{Devaiah N.\} and Josephine Trichka and Jan Wisniewski and Lan Zhou and Qingrong Chen and Daoud Meerzaman and Singer, \{Dinah S.\} and Stanley Adoro",

note = "{\textcopyright} 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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month = dec,

doi = "10.1038/s41467-025-59504-9",

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T1 - The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription

AU - Umphred-Wilson, Katharine

AU - Ratnayake, Shashikala

AU - Tang, Qianzi

AU - Wang, Rui

AU - Chaudhary, Sneha Ghosh

AU - Ballachanda, Devaiah N.

AU - Trichka, Josephine

AU - Wisniewski, Jan

AU - Zhou, Lan

AU - Chen, Qingrong

AU - Meerzaman, Daoud

AU - Singer, Dinah S.

AU - Adoro, Stanley

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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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KW - Animals

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KW - Receptor, Notch1/metabolism

KW - E1A-Associated p300 Protein/metabolism

KW - Leukemia, T-Cell/genetics

KW - p300-CBP Transcription Factors/metabolism

KW - Bromodomain Containing Proteins

KW - Nuclear Proteins

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JF - Nature Communications

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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