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

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.

doi:10.1074/jbc.m114.569889

Cited by 56 publications

(47 citation statements)

References 45 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recurrent mutations or deletions have been identified in 19% of primary central nervous system lymphoma cases, Sezary syndrome, and 2/9 ABC-type DLBCLs [39–42]. TBL1XR1 disrupts glucocorticoid receptor recruitment to the chromatin and results in glucocorticoid resistance in B-ALL [43]. Our study revealed that TBL1XR1 mutation at the WD40 domain facilitates binding with NCoR , leading to increased degradation of the NCoR complex, which results in activation of the NF-κB and c-Jun pathways.…”

Section: Discussionmentioning

confidence: 99%

The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP

et al. 2017

View full text Add to dashboard Cite

Ocular marginal zone lymphoma is a common type of low-grade B-cell lymphoma. To investigate the genomic changes that occur in ocular marginal zone lymphoma, we analyzed 10 cases of ocular marginal zone lymphoma using whole-genome and RNA sequencing and an additional 38 cases using targeted sequencing. Major genetic alterations affecting genes involved in nuclear factor (NF)-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B-cell differentiation (23%) were identified. In whole-genome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in 5 samples (50%). In addition, 5 structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region was found in 3 samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), cAMP response element binding proteins (CREBBP) (17%) and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms genes involving in the activation of the NF-kB signaling pathway is the major driver in the oncogenesis of ocular MZL.

show abstract

Section: Discussionmentioning

confidence: 99%

The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP

et al. 2017

View full text Add to dashboard Cite

show abstract

“…GR is subject to various post-translational modifications , which can mediate subcellular trafficking, promoter specificity, cofactor interaction, receptor stability, and turnover [152]. At specific gene loci, the response to glucocorticoids is regulated by the recruitment of cofactors, which can act in varying mechanisms, including: remodeling the chromatin, facilitating the assembly of transcriptional machinery, or modifying histones or other components of the transcription factor complex [153–156]. These coregulators of GR function maintain tissue-specific expression [157, 158].…”

Section: Figurementioning

confidence: 99%

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

Whirledge

Cidlowski

2017

Trends in Endocrinology & Metabolism

135

103

View full text Add to dashboard Cite

Glucocorticoids are steroid hormones that regulate diverse cellular functions and are essential to facilitate normal physiology. Yet, stress-induced levels of glucocorticoids result in several pathologies including profound reproductive dysfunction. Compelling new evidence indicates glucocorticoids are crucial to the establishment and maintenance of reproductive function. The fertility promoting or inhibiting activity of glucocorticoids depends on timing, dose, and glucocorticoid-responsiveness within a given tissue, which is mediated by the glucocorticoid receptor. The glucocorticoid receptor gene and protein are subject to cellular processing, contributing to signaling diversity and providing a mechanism by which both physiological and stress-induced levels of glucocorticoids function in a cell-specific function. Understanding how glucocorticoids regulate fertility and infertility may lead to novel approaches to the regulation of reproductive function.

show abstract

“…Viral preparation, genome-wide shRNA screening, 17 real-time quantitative polymerase chain reaction, 18 apoptosis assays, 18 cell viability assays, 18 immunoblots, 18 phospho flow cytometry, 19 and xenograft models [20][21][22][23] were all performed as previously described with additional details and modifications available in the supplemental Methods, found on the Blood Web site.…”

Section: Additional Methodsmentioning

confidence: 99%

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia

Jones

Gearheart

Fosmire

et al. 2015

Blood

Self Cite

View full text Add to dashboard Cite

• Genetic or pharmacologic inhibition of MEK4 and MEK2 enhances prednisoloneinduced cell death in ALL models.• MAPK signaling cascades are activated at relapse compared to diagnosis in ALL samples and have enhanced response to MEK inhibition.The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease. (Blood. 2015;126(19):2202-2212

show abstract

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

Cited by 56 publications

References 45 publications

The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP

The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia

Contact Info

Product

Resources

About