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Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia.

ABSTRACT: Treatment outcomes in children with acute lymphoblastic leukemia (ALL) have been improved substantially, with a cure rate exceeding 80% using conventional therapy. However, the outcome for patients with relapsed/refractory ALL remains unsatisfactory, despite the fact that these patients generally receive more intense therapy. Glucocorticoid (GC) resistance is a leading cause of treatment failure and relapse in ALL. Abnormal NR3C1 transcription and/or translation is strongly associated with GC resistance, but the underlying molecular mechanism and the clinical value of NR3C1 alterations with GC resistance in ALL treatment remain unclear. This study applied panel sequencing to 333 newly diagnosed and 18 relapsed ALL samples to characterize the link between NR3C1 and ALL further. We identified NR3C1 mutations in three patients with newly diagnosed ALL (0.9%) and two patients with relapsed ALL (11.1%). Functional analyses revealed that four of these five NR3C1 mutations (p. R477H, p. Y478C, p. P530fs, and p. H726P) were loss-of-function (LoF) mutations. A drug sensitivity test further showed that LoF NR3C1 mutations influence GC resistance. Saturated mutagenesis of hotspot R477 demonstrated the importance of this residue for NR3C1 function. The dominant-negative effect of p. R477C and p. R477S and the non-dominant negative effect of p. R477H and p. Y478C suggests multiple mechanisms underlying GC resistance. Thus, primary or acquired genomic lesions in NR3C1 may play a critical role in GC resistance and contribute to ALL treatment failure and/or relapse.

SUBMITTER: Liu H

PROVIDER: S-EPMC8039513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some "truly" re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors ("off-target effects"), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.

Project description:BackgroundGlucocorticoids are used in the curative treatment of acute lymphoblastic leukemia (ALL). Resistance to glucocorticoids is an important adverse prognostic factor in newly diagnosed ALL patients but its mechanism is unknown. Because SWI/SNF complex-mediated chromatin remodeling is required for glucocorticoid transcriptional activity in vitro, we investigated whether expression of subunits of the SWI/SNF complex was related to glucocorticoid resistance in ALL.MethodsGene expression and in vitro sensitivity to prednisolone and dexamethasone were assessed in a training set of primary ALL cells from 177 children with newly diagnosed ALL and a validation set of cells from an independent cohort of 95 ALL patients. The global test method was used to select pathways whose genes were associated with drug sensitivity. Genes involved in chromatin remodeling were identified by use of the Gene Ontology database. Short hairpin RNA (shRNA) was used to knock down mRNA expression of SMARCA4 in glucocorticoid-sensitive Jurkat human ALL cells. Spearman rank correlation, multiple linear regression, and logistic regression were used to investigate associations between gene expression and glucocorticoid sensitivity. All statistical tests were two-sided.ResultsStatistically significant associations between decreased expression in ALL cells of genes for core subunits of the SWI/SNF complex-SMARCA4, ARID1A, and SMARCB1-and resistance to prednisolone and dexamethasone were identified in the training cohort. In the validation cohort, expression of SMARCA4 (P < .001 and r = -0.43), ARID1A (P = .016 and r = -0.29), and SMARCB1 (P = .019 and r = -0.29) in ALL cells was statistically significantly associated with dexamethasone sensitivity, and SMARCA4 expression (P = .018 and r = -0.28) was statistically significantly associated with prednisolone sensitivity. Prednisolone resistance was higher in SMARCA4 shRNA-transfected Jurkat cells (drug concentration lethal to 50% of the leukemia cells [LC(50)] = 277 microM) than in control shRNA-transfected cells (LC(50) = 174 microM, difference = 103 microM, 95% confidence interval of the difference = 100 to 106 microM; P < .001, t test).ConclusionDecreased expression of as many as three subunits of the SWI/SNF complex appears to be associated with glucocorticoid resistance in primary ALL cells.

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Association Between NR3C1 Mutations and Glucocorticoid Resistance in Children With Acute Lymphoblastic Leukemia.

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