PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia
Open accessPublished version of a preprint
Abstract
Abstract The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularlythe eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic.
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“Mutations in various genes deregulating different signaling pathways 33 – 36 have been associated with the dysregulation of BIM and glucocorticoidresistance.”
Self-citationEarly-life imprinting of unconventional T cells and tissue homeostasis
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“We have published a series of studies on epigenetic inhibition of the pro-apoptotic BIM gene associated with glucocorticoid resistance inALL 18,26,28,59,60 .”
Self-citationPre-established Chromatin Interactions Mediate the Genomic Response to Glucocorticoids
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BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia.
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“For instance, loss of BTG1 or PTEN can cause gluco-corticoidresistancebyinhibitingGRexpressionortranslocationtothe nucleus 31,32 , but primary ALL cells rarely show blocked GR function 26 .”
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“For example, MIZ-1 (encoded by ZBTB17 ) regulates B-cell differentiation at early progenitor stages 75 , while PLZF (encoded by ZBTB16 ) directs differentiation of the NKT cell lineage 52 and ZBTB16 translocations have been reported critical in driving leukemogenesis, such as ZBTB16-RARA in acute…”
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Self-citationTranscriptomic classes of BCR-ABL1 lymphoblastic leukemia
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“…stem cells have been identi fi ed as the initiators of chemo-resistance and relapse in various tumor types 61 – 63 including acute myeloid leukemia, lymphoid cells at various developmental stages havebeenimplicatedin key aspects of ALL, such as oncogenesis, chemo-resistance, and relapse 64 – 69 .”
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Self-citationHuman genome-wide measurement of drug-responsive regulatory activity
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“The GR binding further induces chromatin conformation changes to form transcriptionally active DNA loops, also known as topologically associated domains (TADs) 15 – 17 .”
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Cohesin mutations in myeloid malignancies
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Self-citationDefining B Cell Chromatin: Lessons from EBF1.
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“Furthermore, glucocorticoid resistance driven by different mutations harbored a similar mechanism: aberrant chromatin accessibility 20,21 .”
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“The fi delity of all PDXs is routinely validated by high-density SNP (single nucleotide polymorphism) arrays as previously described 24 .”
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“54 )was used to calculate a log-odds scoreforGR-LSOs and non-GR-LSOs using theannotatedpeaksfunctionfromtheHomerpackagewiththe-mand -mscore options enabled 38 .”
Self-citationTemporal autoregulation during human PU.1 locus SubTAD formation.
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RCAN1 Is an Important Mediator of Glucocorticoid-Induced Apoptosis in Human Leukemic Cells
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“…itself (as a GR dimer) and proteins involved in structural and enzyme-interacting, chromatin-remodeling, methyltransferases, histone acetyltransferase/deacetylase, and TFs. Previous work has iden-ti fi ed long-range GR interactions depend on interaction with members of the cohesin complex 46 – 48 .”
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Chen, J., Mo, J., Wei, J., Qu, M., Dai, J., Kong, Y., Xu, H., Li, J., Yan, X., Cui, C., et al. (2025) · Advanced Science · doi:10.1002/advs.202514600 · Cited by 7 · see citing works
Advances in the application of patient-derived xenograft models in acute leukemia resistance
Qin, R.-H., Liang, Y.-X., & Zhou, F.-L. (2025) · Cancer Drug Resistance · doi:10.20517/cdr.2025.18 · Cited by 6 · see citing works
Differential regulation of type 2 immunity by glucocorticoids
Song, H., & Lim, J. (2025) · BMB Reports · doi:10.5483/bmbrep.2025-0066 · Cited by 2
Abdoul-Azize, S., Vannier, J.-P., & Schneider, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083489 · Cited by 2
“However, in ALL, GCs may paradoxically promote resistance [1,11,12].”
Glucocorticoid receptor biology through the omics lens: context matters
Singh, P., & Greulich, F. (2026) · Biological chemistry · doi:10.1515/hsz-2026-0147 · Cited by 1 · see citing works
“Follow-up work further implicated the Spi-1 proto-oncogene PU.1/SPI1 as a priming factor at lymphocyte-speci fi c GC-response domains and super-enhancers, with PU.1/SPI1-mediated nucleosome eviction facilitating GR loading and apoptotic gene induction (Beck et al. 2024).”
Enhancer Poising Enables Pathogenic Gene Activation by Noncoding VariantsPreprint
Hollingsworth, E. W., Chen, Z., Chen, C. X., Jacinto, S. H., Liu, T. A., & Kvon, E. Z. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.20.660819 · Cited by 1 · see citing works
“…of gene expression during lineage specification (Rada-Iglesias et al. 2011; Crispatzu et al. 2021; Bogdanovic et al. 2012; Bonn et al. 2012; Wamstad et al. 2012; Calo and Wysocka 2013; Creyghton et al. 2010) and in response to external cues (Zaret, Lerner, and Iwafuchi-Doi 2016; Beck et al. 2024).”
Glucocorticoid Insensitivity: Is It a Question of Time and Place?
Lambers, C., & Roth, M. (2025) · Biomedicines · doi:10.3390/biomedicines13061418 · Cited by 1 · see citing works
Xu, W., Ma, X.-F., Sun, X., Song, G., Zhu, S.-H., Tian, J., Shi, R.-R., & Guo, L.-L. (2026) · Cancer Research · doi:10.1158/0008-5472.can-25-3743
“1D ), and PU.1 was identified as a putative transcription factor, which is consistent with our previous findings that PU.1 binds to LSEs and mediates the drug response in ALL cells (19).”
Self-citationCase Report: A novel de novo SPI1 mutation identified in a Chinese patient with agammaglobulinemia
Peng, Q., Deng, M., Zeng, X., Cheng, Q., Xie, M., Li, S., & Lu, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1716208
- Authors
- 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., Bridge, K. S., Zhang, C., Wang, J., Mi, J.-Q., Lock, R. B., de Bock, C. E., & Jing, D.
- Affiliations
- University of Technology Sydney (AU)
- Shanghai Jiao Tong University (CN)
- Hebei University of Engineering (CN)
- UNSW Sydney (AU)
- University of York (GB)
- Albert Einstein College of Medicine (US)
- The University of Sydney (AU)
- Corresponding author
- Beck, Dominik
- Lock, Richard B.
- Jing, Duohui
- ORCID
- Venue
- Nature Communications
- Published
- 2024-11-08
- Volume
- 15
- Issue
- 1
- Pages
- 9697-9697
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11549222
- OpenAlex
- W4404167560
- Cited by
- 9
- References
- 104
- Citations by year
- 2026: 3 · 2025: 6
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OPUS - Open Publications of UTS Scholars (University of Technology Sydney) (submittedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Neuroscience Research Australia
- Yorkshire Forward (EP/K039660/1, EP/M028127/1)
- Kay Kendall Leukaemia Fund (KKL1377)
- Research Councils UK (EP/K039660/1, EP/M028127/1)
- Deutsche Forschungsgemeinschaft (EP/M028127/1, EP/K039660/1)
- University of New South Wales
- University of Sydney
- University of Technology Sydney
- National Natural Science Foundation of China (82270155, 32271165, 82270187, 82070227, 82050410359, 82070144)
- Science and Technology Commission of Shanghai Municipality (21430711800, 23141903000)
- Shanghai Jiao Tong University
- Hebei University
- Chinesisch-Deutsche Zentrum für Wissenschaftsförderung
- Hebei University of Engineering
- Kids Cancer Alliance
- Ruijin Hospital
- Translational Cancer Research Network
- Centre for Blood Research, University of British Columbia
- Medical Research Council
- Engineering and Physical Sciences Research Council (EP/M028127/1, EP/K039660/1)
- Biotechnology and Biological Sciences Research Council (BB/Y51424X/1, BB/X018288/1, EP/M028127/1, BB/W019272/1, EP/K039660/1, BB/V000071/1)
- National Health and Medical Research Council (1181666, 1157871)
- School of Medicine, Shanghai Jiao Tong University
- Faculty of Medicine and Health, University of Sydney
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- PU.1, glucocorticoid resistance, acute lymphoblastic leukemia, glucocorticoid receptor, chromatin organization, pioneer transcription factors, epigenetic regulation, apoptosis, drug response
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Chromatin, Female, Glucocorticoids, Humans, Lymphocytes, Proto-Oncogene Proteins, Receptors, Glucocorticoid, Trans-Activators, Gene Expression Regulation, Leukemic, Apoptosis, Drug Resistance, Neoplasm, Response Elements, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Cell Line, Tumor, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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