Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis

Gruber, Georg B.; Carlet, Michela; Türtscher, E; Meister, Bernhard; Irving, Julie; Ploner, Christian; Kofler, Reinhard

doi:10.1038/leu.2008.360

Cited by 40 publications

(33 citation statements)

References 7 publications

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“…30 It has been recently shown that dexamethasone induces cellular death by autophagy; 31 however, the mechanisms underlying response to corticosteroids are complex and not fully understood. 30, 32, 33, 34 Given that JQ1 downregulates multiple pro-survival genes that differ from GS targets 35 (Supplementary Figure 4), we hypothesised that low doses of JQ1 would sensitise ALL cells to killing by dexamethasone. Indeed, significant sensitisation was observed in vitro , in two dexamethasone-resistant cell lines, NALM-17 and REH (Figure 7a).…”

Section: Resultsmentioning

confidence: 99%

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

Costa

Agathanggelou

Perry

et al. 2013

Blood Cancer Journal

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Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.

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Section: Resultsmentioning

confidence: 99%

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

Costa

Agathanggelou

Perry

et al. 2013

Blood Cancer Journal

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“…This finding, however, is at odds with another study showing that phosphorylation of S134 is able to translocate to the nucleus, but alters gene expression [39]. In other studies, a failure to increase GR levels through a positive feedback loop has been shown to impair GC induced apoptosis, though how this feedback is disrupted has not been established [40, 41]. Lastly, not all GR isoforms have the ability to induce apoptosis, suggesting that mechanisms that regulate isoform selection may play a role [42].…”

Section: Lymphoid Cancersmentioning

confidence: 98%

Glucocorticoids and Cancer

Pufall¹

2015

Advances in Experimental Medicine and Biology

175

116

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Unlike other steroid hormone receptors, the glucocorticoid receptor (GR) is not considered an oncogene. In breast cancer, the estrogen receptor (ER) drives cell growth, proliferation, and metastasis, and the androgen receptor (AR) plays a similar role in prostate cancer. Accordingly, treatment of these diseases has focused on blocking steroid hormone receptor function. In contrast, glucocorticoids (GCs) work through GR to arrest growth and induce apoptosis in lymphoid tissue. Glucocorticoids are amazingly effective in this role, and have been deployed as the cornerstone of lymphoid cancer treatment for decades. Unfortunately, not all patients respond to GCs and dosage is restricted by immediate and long term side effects. In this chapter we review the treatment protocols that employ glucocorticoids as a curative agent, elaborate on what is known about their mechanism of action in these cancers, and also summarize the palliative uses of glucocorticoids for other cancers.

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“…20 Although the mode of GC resistance has been the subject of controversial discussions for a long time, recent evidence suggests that the GC receptor expression level, as well as the GC-induced regulation of both proapoptotic and antiapoptotic BCL2 family member-dependent pathway components, plays a major role. 29,48 Minimal residual disease response evaluation in 3 of our NR3C1-deleted cases revealed a poor blast cell clearance in the BM after 2 months of treatment with equal or more than 10 Ϫ3 cells, a leukemic cell load that is currently used as indication for stem cell transplantation in BFM-based therapy protocols. 49 NR3C1 deletions acquired at relapse were not considered as sole progression markers because other genomic alterations that were present at diagnosis had not been retained.…”

Section: Discussionmentioning

confidence: 99%

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

Kuster

Grausenburger

Fuka

et al. 2011

Blood

101

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Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P ‫؍‬ .01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n ‫؍‬ 3), glucocorticoid receptor NR3C1 (n ‫؍‬ 4), and components of the mismatch repair pathways (n ‫؍‬ 3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/ RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P ‫؍‬ .02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies. (Blood. 2011;117(9):2658-2667)

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Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis

Cited by 40 publications

References 7 publications

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia

Glucocorticoids and Cancer

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

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