title: Loss of TBL1XR1 disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance in a B-lymphoblastic leukemia model.
abstract: Although great advances have been made in the treatment of pediatric acute lymphoblastic leukemia, up to one of five patients will relapse, and their prognosis thereafter is dismal. We have previously identified recurrent deletions in TBL1XR1, which encodes for an F-box like protein responsible for regulating the nuclear hormone repressor complex stability. Here we model TBL1XR1 deletions in B-precursor ALL cell lines and show that TBL1XR1 knockdown results in reduced glucocorticoid receptor recruitment to glucocorticoid responsive genes and ultimately decreased glucocorticoid signaling caused by increased levels of nuclear hormone repressor 1 and HDAC3. Reduction in glucocorticoid signaling in TBL1XR1-depleted lines resulted in resistance to glucocorticoid agonists, but not to other chemotherapeutic agents. Importantly, we show that treatment with the HDAC inhibitor SAHA restores sensitivity to prednisolone in TBL1XR1-depleted cells. Altogether, our data indicate that loss of TBL1XR1 is a novel driver of glucocorticoid resistance in ALL and that epigenetic therapy may have future application in restoring drug sensitivity at relapse.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Jones
authors.forename: Teena
authors.initials: T
authors.lastname: Bhatla
authors.forename: Roy
authors.initials: R
authors.lastname: Blum
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Steven W
authors.initials: SW
authors.lastname: Paugh
authors.forename: Xin
authors.initials: X
authors.lastname: Wen
authors.forename: Wallace
authors.initials: W
authors.lastname: Bourgeois
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Bitterman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Morrison
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D005938:Glucocorticoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D002843:Chromatin; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C473691:TBL1XR1 protein, human