Loss of TBL1XR1 Disrupts Glucocorticoid Receptor Recruitment to Chromatin and Results in Glucocorticoid Resistance in a B-lymphoblastic Leukemia Model

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 Jun 5

PMID 24895125

Citations 35

Authors

Courtney L Jones

Teena Bhatla

Roy Blum

Jinhua Wang

Steven W Paugh

Xin Wen

Wallace Bourgeois

Danielle S Bitterman

Elizabeth A Raetz

Debra J Morrison

David T Teachey

William E Evans

Michael J Garabedian

William L Carroll

Affiliations

Soon will be listed here.

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.

Citing Articles

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