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

Author

Listed:
  • Katharine Umphred-Wilson

    (National Institutes of Health
    Case Western Reserve University School of Medicine)

  • 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
    Case Western Reserve University School of Medicine)

  • 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)

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.

Suggested Citation

  • Katharine Umphred-Wilson & Shashikala Ratnayake & Qianzi Tang & Rui Wang & Sneha Ghosh Chaudhary & Devaiah N. Ballachanda & Josephine Trichka & Jan Wisniewski & Lan Zhou & Qingrong Chen & Daoud Meerza, 2025. "The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59504-9
    DOI: 10.1038/s41467-025-59504-9
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