Differential mRNA expression of glucocorticoid receptor α and β is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children

Koga, Yuhki; Matsuzaki, Akinobu; Suminoe, Aiko; Hattori, Hiroyoshi; Kanemitsu, Shigeru; Hara, Toshiro

doi:10.1002/pbc.20308

Cited by 53 publications

(42 citation statements)

References 26 publications

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“…GRh has been reported to suppress transactivation of GRa by synthetic glucocorticoids, and high levels of GRh may correlate with insensitivity to glucocorticoid-induced apoptosis (33,34). We therefore examined GRh regulation by PDE4 inhibitors in B-CLL.…”

Section: Resultsmentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Meyers

Taverna

Chaves

et al. 2007

Clinical Cancer Research

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Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GRa) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRa transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRa mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRa transcription. Rolipram treatment increases levels of transcripts derived from the1A3 promoter to a greater extent than the 1B promoter.Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR upregulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRa transcript levels in a dose-related manner, cotreatment with rolipram maintained GRa transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor^mediated up-regulation of GRa expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.Glucocorticoids are an important component of standard therapy for several lymphoid malignancies, including multiple myeloma, acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. As early studies in patients with B-cell chronic lymphocytic leukemia (B-CLL) showed that addition of prednisone to chlorambucil augmented response rate but not median survival, glucocorticoids are not generally a standard component of initial therapy for patients with B-CLL (1, 2). Nonetheless, two studies of high-dose glucocorticoid therapy have suggested that glucocorticoids can be of clinical benefit to a subset of patients with treatment-refractory B-CLL (3, 4).Despite frequent responses to glucocorticoid treatment, monotherapy with glucocorticoids is not curative in any lymphoid malignancy, but the mechanisms underlying clinical glucocorticoid resistance remain controversial. Structural alterations in the glucocorticoid receptor (GR) are commonly identified in lymphoid cell lines that have been selected for glucocorticoid resistance by prolonged culture in dexamethasone, but comparable alterations in primary malignant lymphoid cells have been only infrequently reported (5 -9). A detailed analysis of treated B-CLL patients failed to identify abnormalities in either the DNA-or steroid-binding domains of leukemic GRs (10). Nonstructural modifications of ...

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Section: Resultsmentioning

confidence: 99%

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Meyers

Taverna

Chaves

et al. 2007

Clinical Cancer Research

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“…Previous studies have shown that the GR␤ isoform can inhibit glucocorticoid signaling in a dominant-negative fashion by heterodimerization with GR␣ (33,34). Increased GR␤ production has been associated with glucocorticoid resistance in immune system diseases including asthma and acute lymphoblastic leukemia (35,36). Interestingly, the rs6198 A/G polymorphism that shows strong associations with BP traits in EA is located in exon 9␤, disrupting a consensus sequence element in the 3Ј UTR that is known to destabilize mRNA.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Gene Variant in the 3′ Untranslated Region Is Associated with Multiple Measures of Blood Pressure

Chung

Shimmin

Natarajan

et al. 2009

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context:The glucocorticoid receptor (GR) is a key hormone in the hypothalamus-pituitary-adrenal axis that regulates many pathways including blood pressure homeostasis. Thus, GR gene variation may influence interindividual differences in blood pressure in human populations. Objective:We resequenced individual GR alleles for comprehensive discovery of GR variants and their chromosomal phase in three major American ethnic groups. We examined the influence of GR variants on blood pressure in large numbers of families using family-based association methods. Design and Participants:For association studies, we genotyped GR variants in family members from the Genetic Epidemiology Network of Arteriopathy (GENOA) study that were measured for multiple blood pressure traits. The GENOA families consisted of African-Americans, Mexican-Americans, and European-Americans. Main Measurements:The blood pressure measurements for association studies included systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure.Results: Single-nucleotide polymorphisms (SNPs) identified by resequencing were tested for associations with blood pressure measures in GENOA families. Analysis of individual SNPs identified significant associations of rs6198 A/G in exon 9␤ with multiple blood pressure measures in European-Americans. Analysis of GR haplotypes found significant associations of a haplotype that is distinguished by rs6198 A/G. Conclusions:Significant associations of blood pressure with rs6198 A/G likely reflect allelic effects on GR signaling. This SNP disrupts a 3Ј untranslated region sequence element in exon 9␤ that destabilizes mRNA, resulting in increased production of the inactive GR␤ isoform. Excess heterodimerization with the active GR␣ isoform may reduce GR signaling with subsequent physiological effects on blood pressure regulation. (J Clin Endocrinol Metab 94: 268 -276, 2009)

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“…GRβ levels are also elevated in glucocorticoid-resistant cases of asthma [51], rheumatoid arthritis [52], ulcerative colitis [53], and systemic lupus erythematosus [54]. High GRβ expression is also associated with glucocorticoid resistance in acute lymphoblastic leukemia and chronic lymphocytic leukemia [55, 56]. Manipulating GRα/GRβ expression ratios, therefore, may provide a means to modulate glucocorticoid sensitivity.…”

Section: The Glucocorticoid Receptormentioning

confidence: 99%

Specificity and sensitivity of glucocorticoid signaling in health and disease

Cain

Cidlowski

2015

Best Practice & Research Clinical Endocrinology & Metab

111

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Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and induced biological responses across tissues. The immunoregulatory properties of glucocorticoids are exploited in the clinic for the treatment of inflammatory and autoimmune disorders as well as certain hematological malignancies, but adverse side effects hamper prolonged use. Fully understanding the molecular events that shape the physiologic effects of glucocorticoid treatment will provide insight into optimal glucocorticoid treatments, reliable assessment of glucocorticoid sensitivity in patients, and may advance the development of novel GR agonists that exert immunosuppressive effects while avoiding harmful side effects. In this review, we provide an overview of mechanisms that affect glucocorticoid specificity and sensitivity in health and disease, focusing on the distinct isoforms of the glucocorticoid receptor and their unique regulatory and functional properties.

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Differential mRNA expression of glucocorticoid receptor α and β is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children

Abstract: The amounts of GR isoform mRNA in leukemic blasts were closely correlated with sensitivity to glucocorticoid exposure. The mRNA expression pattern of GR isoforms at initial presentation may provide valuable information for prognosis in children with newly diagnosed ALL.

Cited by 53 publications

References 26 publications

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells

Glucocorticoid Receptor Gene Variant in the 3′ Untranslated Region Is Associated with Multiple Measures of Blood Pressure

Specificity and sensitivity of glucocorticoid signaling in health and disease

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