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

• Published in: The Journal of biological chemistry 2014-07, Vol.289 (30), p.20502-20515
• Main Authors: Jones, Courtney L., Bhatla, Teena, Blum, Roy, Wang, Jinhua, Paugh, Steven W., Wen, Xin, Bourgeois, Wallace, Bitterman, Danielle S., Raetz, Elizabeth A., Morrison, Debra J., Teachey, David T., Evans, William E., Garabedian, Michael J., Carroll, William L.
• Format: Article
• Language: English
• Subjects: Acute Lymphoblastic Leukemia; Adolescent; Cancer Biology; Cell Line, Tumor; Chemoresistance; Child; Child, Preschool; Chromatin - genetics; Chromatin - metabolism; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Glucocorticoid; Glucocorticoids - pharmacology; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Leukemia; Male; Models, Biological; Molecular Bases of Disease; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Relapsed Childhood Leukemia; Repressor Proteins - genetics; Repressor Proteins - metabolism; TBL1XR1 Deletions; Transcription Corepressor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.569889

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. Background: Resistance to glucocorticoid agonists is a major challenge in the treatment of pediatric leukemia. Results: TBL1XR1 knockdown decreases glucocorticoid signaling and response in leukemia cells. Conclusion: Deletions in TBL1XR1 at relapse may drive resistance to glucocorticoid agonists. Significance: Identifying drivers of glucocorticoid resistance in leukemia may allow for the identification of novel therapies for the treatment of recurrent disease.