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

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

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

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

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Nat Commun, 2024, 15, (1), pp. 9697
Issue Date:: 2024-11-08

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Field	Value	Language
dc.contributor.author	Beck, D
dc.contributor.author	Cao, H
dc.contributor.author	Tian, F
dc.contributor.author	Huang, Y
dc.contributor.author	Jiang, M
dc.contributor.author	Zhao, H
dc.contributor.author	Tai, X
dc.contributor.author	Xu, W
dc.contributor.author	Kosasih, HJ
dc.contributor.author	Kealy, DJ
dc.contributor.author	Zhao, W
dc.contributor.author	Taylor, SJ
dc.contributor.author	Couttas, TA
dc.contributor.author	Song, G
dc.contributor.author	Chacon-Fajardo, D
dc.contributor.author	Walia, Y
dc.contributor.author	Wang, M
dc.contributor.author	Dowle, AA
dc.contributor.author	Holding, AN
dc.contributor.author	Bridge, KS
dc.contributor.author	Zhang, C
dc.contributor.author	Wang, J
dc.contributor.author	Mi, J-Q
dc.contributor.author	Lock, RB
dc.contributor.author	de Bock, CE
dc.contributor.author	Jing, D
dc.date.accessioned	2025-01-28T05:23:57Z
dc.date.available	2024-10-29
dc.date.available	2025-01-28T05:23:57Z
dc.date.issued	2024-11-08
dc.identifier.citation	Nat Commun, 2024, 15, (1), pp. 9697
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/184315
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-024-54096-2
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Humans
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Animals
dc.subject.mesh	Trans-Activators
dc.subject.mesh	Chromatin
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	Mice
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Lymphocytes
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Apoptosis
dc.subject.mesh	Response Elements
dc.subject.mesh	Epigenesis, Genetic
dc.subject.mesh	Gene Expression Regulation, Leukemic
dc.subject.mesh	Female
dc.subject.mesh	Lymphocytes
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Chromatin
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Trans-Activators
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Apoptosis
dc.subject.mesh	Epigenesis, Genetic
dc.subject.mesh	Gene Expression Regulation, Leukemic
dc.subject.mesh	Response Elements
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Female
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Humans
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Animals
dc.subject.mesh	Trans-Activators
dc.subject.mesh	Chromatin
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Proto-Oncogene Proteins
dc.subject.mesh	Mice
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Lymphocytes
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Apoptosis
dc.subject.mesh	Response Elements
dc.subject.mesh	Epigenesis, Genetic
dc.subject.mesh	Gene Expression Regulation, Leukemic
dc.subject.mesh	Female
dc.title	PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia.
dc.type	Journal Article
utslib.citation.volume	15
utslib.location.activity	England
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-01-28T05:23:54Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	15
utslib.citation.issue	1

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/184315