Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia

Jing, D; Huang, Y; Liu, X; Sia, KCS; Zhang, JC; Tai, X; Wang, M; Toscan, CE; McCalmont, H; Evans, K; Mayoh, C; Poulos, RC; Span, M; Mi, J; Zhang, C; Wong, JWH; Beck, D; Pimanda, JE; Lock, RB

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia

Jing, D Huang, Y

Liu, X Sia, KCS Zhang, JC Tai, X Wang, M Toscan, CE McCalmont, H Evans, K Mayoh, C Poulos, RC Span, M Mi, J Zhang, C Wong, JWH Beck, D Pimanda, JE Lock, RB

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Publication Type:: Journal Article
Citation:: Cancer Cell, 2018, 34 (6), pp. 906 - 921.e8
Issue Date:: 2018-12-10

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Field	Value	Language
dc.contributor.author	Jing, D	en_US
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110	en_US
dc.contributor.author	Liu, X	en_US
dc.contributor.author	Sia, KCS	en_US
dc.contributor.author	Zhang, JC	en_US
dc.contributor.author	Tai, X	en_US
dc.contributor.author	Wang, M	en_US
dc.contributor.author	Toscan, CE	en_US
dc.contributor.author	McCalmont, H	en_US
dc.contributor.author	Evans, K	en_US
dc.contributor.author	Mayoh, C	en_US
dc.contributor.author	Poulos, RC	en_US
dc.contributor.author	Span, M	en_US
dc.contributor.author	Mi, J	en_US
dc.contributor.author	Zhang, C	en_US
dc.contributor.author	Wong, JWH	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.contributor.author	Lock, RB	en_US
dc.date.available	2018-11-05	en_US
dc.date.issued	2018-12-10	en_US
dc.identifier.citation	Cancer Cell, 2018, 34 (6), pp. 906 - 921.e8	en_US
dc.identifier.issn	1535-6108	en_US
dc.identifier.uri	http://hdl.handle.net/10453/132141
dc.description.abstract	© 2018 Elsevier Inc. Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types. Jing et al. identified lymphocyte-specific open chromatin domains (LSOs) critical for glucocorticoid (GC)-induced acute lymphoblastic leukemia (ALL) apoptosis. GC receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by DNA methylation in GC-resistant ALL and non-lymphoid cell types.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1073768
dc.relation.ispartof	Cancer Cell	en_US
dc.relation.isbasedon	10.1016/j.ccell.2018.11.002	en_US
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.subject.mesh	Lymphocytes	en_US
dc.subject.mesh	Chromatin	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred NOD	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice, SCID	en_US
dc.subject.mesh	Azacitidine	en_US
dc.subject.mesh	Dexamethasone	en_US
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols	en_US
dc.subject.mesh	Glucocorticoids	en_US
dc.subject.mesh	Xenograft Model Antitumor Assays	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Drug Resistance, Neoplasm	en_US
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma	en_US
dc.title	Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia	en_US
dc.type	Journal Article
utslib.citation.volume	6	en_US
utslib.citation.volume	34	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0903 Biomedical Engineering	en_US
utslib.for	1109 Neurosciences	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
pubs.issue	6	en_US
pubs.publication-status	Published	en_US
pubs.volume	34	en_US

Abstract:

© 2018 Elsevier Inc. Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). This led to the identification of LSOs critical for glucocorticoid-induced apoptosis. Glucocorticoid receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by increased DNA methylation in glucocorticoid-resistant ALL and non-lymphoid cell types. Our study demonstrates that lymphocyte-specific epigenetic modifications pre-determine glucocorticoid resistance in ALL and may account for the lack of glucocorticoid sensitivity in other cell types. Jing et al. identified lymphocyte-specific open chromatin domains (LSOs) critical for glucocorticoid (GC)-induced acute lymphoblastic leukemia (ALL) apoptosis. GC receptor cooperated with CTCF at these LSOs to mediate DNA looping, which was inhibited by DNA methylation in GC-resistant ALL and non-lymphoid cell types.

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

http://hdl.handle.net/10453/132141