PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

Dominik Beck; Honghui Cao; Feng Tian; Yizhou Huang; Miao Jiang; Han Zhao; Xiaolu Tai; Wenqian Xu; Hansen J Kosasih; David J Kealy; Weiye Zhao; Samuel J Taylor; Timothy A Couttas; Gaoxian Song; Diego Chacon-Fajardo; Yashna Walia; Meng Wang; Adam A Dowle; Andrew N Holding; Katherine S Bridge; Chao Zhang; Jin Wang; Jian-Qing Mi; Richard B Lock; Charles E de Bock; Duohui Jing

doi:10.1038/s41467-024-54096-2

PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

Dominik Beck, Honghui Cao, Feng Tian, Yizhou Huang, Miao Jiang, Han Zhao, Xiaolu Tai, Wenqian Xu, Hansen J Kosasih, David J Kealy, Weiye Zhao, Samuel J Taylor, Timothy A Couttas, Gaoxian Song, Diego Chacon-Fajardo, Yashna Walia, Meng Wang, Adam A Dowle, Andrew N Holding, Katherine S BridgeChao Zhang, Jin Wang, Jian-Qing Mi, Richard B Lock, Charles E de Bock, Duohui Jing

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

Abstract

The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Original language	English
Article number	9697
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-54096-2
Publication status	Published - 8 Nov 2024

Bibliographical note

Keywords

Humans
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
Animals
Trans-Activators/metabolism
Chromatin/metabolism
Glucocorticoids/pharmacology
Receptors, Glucocorticoid/metabolism
Proto-Oncogene Proteins/metabolism
Mice
Cell Line, Tumor
Drug Resistance, Neoplasm/genetics
Lymphocytes/metabolism
Xenograft Model Antitumor Assays
Apoptosis/drug effects
Response Elements
Epigenesis, Genetic/drug effects
Gene Expression Regulation, Leukemic/drug effects
Female

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10.1038/s41467-024-54096-2Licence: CC BY-NC-ND

Application of the miniatuRIME method to analyse glucocorticoid receptor complexes in primary healthy and leukaemic T cells
Holding, A. N. (Principal investigator) & Bridge, K. (Co-investigator)
BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL)
27/06/23 → 26/06/25
Project: Research project (funded) › Research

Cite this

Beck, D., Cao, H., Tian, F., Huang, Y., Jiang, M., Zhao, H., Tai, X., Xu, W., Kosasih, H. J., Kealy, D. J., Zhao, W., Taylor, S. J., Couttas, T. A., Song, G., Chacon-Fajardo, D., Walia, Y., Wang, M., Dowle, A. A., Holding, A. N., ... Jing, D. (2024). PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia. Nature Communications, 15, Article 9697. https://doi.org/10.1038/s41467-024-54096-2

@article{cbfe0f8ade19437ebdb439dd3e95f9b2,

title = "PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia",

abstract = "The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.",

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author = "Dominik Beck and Honghui Cao and Feng Tian and Yizhou Huang and Miao Jiang and Han Zhao and Xiaolu Tai and Wenqian Xu and Kosasih, {Hansen J} and Kealy, {David J} and Weiye Zhao and Taylor, {Samuel J} and Couttas, {Timothy A} and Gaoxian Song and Diego Chacon-Fajardo and Yashna Walia and Meng Wang and Dowle, {Adam A} and Holding, {Andrew N} and Bridge, {Katherine S} and Chao Zhang and Jin Wang and Jian-Qing Mi and Lock, {Richard B} and {de Bock}, {Charles E} and Duohui Jing",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = nov,

day = "8",

doi = "10.1038/s41467-024-54096-2",

language = "English",

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Beck, D, Cao, H, Tian, F, Huang, Y, Jiang, M, Zhao, H, Tai, X, Xu, W, Kosasih, HJ, Kealy, DJ , Zhao, W, Taylor, SJ, Couttas, TA, Song, G, Chacon-Fajardo, D, Walia, Y, Wang, M, Dowle, AA, Holding, AN , Bridge, KS, Zhang, C, Wang, J, Mi, J-Q, Lock, RB, de Bock, CE & Jing, D 2024, 'PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia', Nature Communications, vol. 15, 9697. https://doi.org/10.1038/s41467-024-54096-2

TY - JOUR

T1 - PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

AU - Beck, Dominik

AU - Cao, Honghui

AU - Tian, Feng

AU - Huang, Yizhou

AU - Jiang, Miao

AU - Zhao, Han

AU - Tai, Xiaolu

AU - Xu, Wenqian

AU - Kosasih, Hansen J

AU - Kealy, David J

AU - Zhao, Weiye

AU - Taylor, Samuel J

AU - Couttas, Timothy A

AU - Song, Gaoxian

AU - Chacon-Fajardo, Diego

AU - Walia, Yashna

AU - Wang, Meng

AU - Dowle, Adam A

AU - Holding, Andrew N

AU - Bridge, Katherine S

AU - Zhang, Chao

AU - Wang, Jin

AU - Mi, Jian-Qing

AU - Lock, Richard B

AU - de Bock, Charles E

AU - Jing, Duohui

PY - 2024/11/8

Y1 - 2024/11/8

N2 - The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

AB - The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

KW - Humans

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Animals

KW - Trans-Activators/metabolism

KW - Chromatin/metabolism

KW - Glucocorticoids/pharmacology

KW - Receptors, Glucocorticoid/metabolism

KW - Proto-Oncogene Proteins/metabolism

KW - Mice

KW - Cell Line, Tumor

KW - Drug Resistance, Neoplasm/genetics

KW - Lymphocytes/metabolism

KW - Xenograft Model Antitumor Assays

KW - Apoptosis/drug effects

KW - Response Elements

KW - Epigenesis, Genetic/drug effects

KW - Gene Expression Regulation, Leukemic/drug effects

KW - Female

U2 - 10.1038/s41467-024-54096-2

DO - 10.1038/s41467-024-54096-2

M3 - Article

C2 - 39516193

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 9697

ER -

PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

Abstract

Bibliographical note

Keywords

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Projects

Application of the miniatuRIME method to analyse glucocorticoid receptor complexes in primary healthy and leukaemic T cells

Cite this