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dc.contributor.authorGallagher, Kayleigh M.
dc.contributor.authorRoderick, Justine E.
dc.contributor.authorTan, Shi Hao.
dc.contributor.authorTan, Tze King
dc.contributor.authorMurphy, Leonard
dc.contributor.authorYu, Jun
dc.contributor.authorLi, Rui
dc.contributor.authorO'Connor, Kevin W
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorGreen, Michael R.
dc.contributor.authorSanda, Takaomi
dc.contributor.authorKelliher, Michelle A.
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:39Z
dc.date.available2022-08-23T16:49:39Z
dc.date.issued2020-07-13
dc.date.submitted2020-08-05
dc.identifier.citation<p>Gallagher KM, Roderick JE, Tan SH, Tan TK, Murphy L, Yu J, Li R, O'Connor KW, Zhu J, Green MR, Sanda T, Kelliher MA. ESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia. Blood Adv. 2020 Jul 14;4(13):3154-3168. doi: 10.1182/bloodadvances.2020001555. PMID: 32658986; PMCID: PMC7362368. <a href="https://doi.org/10.1182/bloodadvances.2020001555">Link to article on publisher's site</a></p>
dc.identifier.issn2473-9529 (Linking)
dc.identifier.doi10.1182/bloodadvances.2020001555
dc.identifier.pmid32658986
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41506
dc.description.abstractSynthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-beta (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32658986&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © 2020 by The American Society of Hematology. Publisher PDF posted as allowed by the publisher's copyright information page at https://ashpublications.org/bloodadvances/pages/copyright.
dc.subjectLymphoid Neoplasia
dc.subjectacute lymphocytic leukemia
dc.subjectadult t-cell lymphoma/leukemia
dc.subjectdexamethasone
dc.subjectgene expression
dc.subjectgenes
dc.subjectleukemic cells
dc.subjectmice
dc.subjectt-cell leukemia
dc.subjectacute
dc.subjectglucocorticoids
dc.subjectagonists
dc.subjectCancer Biology
dc.subjectNeoplasms
dc.titleESRRB regulates glucocorticoid gene expression in mice and patients with acute lymphoblastic leukemia
dc.typeJournal Article
dc.source.journaltitleBlood advances
dc.source.volume4
dc.source.issue13
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5311&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4285
dc.identifier.contextkey18803795
refterms.dateFOA2022-08-23T16:49:40Z
html.description.abstract<p>Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-beta (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.</p>
dc.identifier.submissionpathoapubs/4285
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.source.pages3154-3168


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