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Glucocorticoid receptors in human leukemias and related diseases
Abstract:
The evidence to date is compelling that steroid initiated cell lysis involves participation of the glucocorticoid receptor. Not only do the concentrations and specificity of hormones for cell lysis and receptor occupancy correspond, but also steroid resistant cells selected with or without prior mutagenesis often have altered receptors. The glucocorticoid receptor protein from humans and other species is a approximately 95,000 d, thiol group-containing monomer, prone to aggregation when "unactivated." After having bound steroid and been "activated," the monomeric steroid-receptor complex is altered in charge and shape so that its binding to chromatin and DNA is greatly enhanced. Simple measurement of numbers of receptor sites in cells from patients with various blood dyscrasias has given, in some disease, good correlations between high numbers of receptor sites and good therapeutic response. These correlations are strongest for childhood acute lymphoblastic leukemia (ALL) and for non Hodgkins' lymphoma. In other diseases, notably acute myelogenous leukemia, such correlations have not been found. The CEM human ALL line has been used in vitro to study mechanisms of glucocorticoid action and resistance. The requirement for "activated" steroid-receptor complex for cell lysis is shown in these cells by the spontaneous occurrence of steroid resistant, activation-labile receptor mutants. A second category of resistant cells with normal receptors has been defined. Treatment of these "lysis defective" resistant cells with compounds which result in DNA demethylation can render them steroid sensitive. Since DNA demethylation can allow formerly silent genes to become transcribed, it is possible that one or more genes specific for lysis has been "opened" in such cells. Alternatively, DNA demethylation may produce a general biochemical effect on the cell which renders it susceptible to lysis. Mutagenized CEM cells selected for steroid resistance give rise to a third class of mutants, which are deficient in receptor quantity. Each of these classes of steroid resistant cells contains information pertinent to understanding the use of glucocorticoids and the role of glucocorticoid receptors in human leukopathic disease.
Insights
Glucocorticoid receptors are crucial for steroid-induced cell death, particularly in childhood acute lymphoblastic leukemia (ALL). Understanding receptor function and resistance mechanisms can improve cancer therapy.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Glucocorticoid receptor (GR) is implicated in steroid-induced cell lysis.
- Steroid resistance in cancer cells often involves altered GR.
- GR is a ~95 kDa monomer that requires activation by steroid binding for enhanced DNA binding.
Purpose of the Study:
- To investigate the role of glucocorticoid receptors in steroid-induced cell lysis.
- To explore mechanisms of steroid resistance in cancer cells.
- To correlate GR numbers with therapeutic response in various blood dyscrasias.
Main Methods:
- Studied human acute lymphoblastic leukemia (ALL) cell lines (CEM) in vitro.
- Selected and characterized steroid-resistant cell mutants.
- Investigated the effect of DNA demethylation on steroid sensitivity.
Main Results:
- Correlations between high GR numbers and therapeutic response are strongest in childhood ALL and non-Hodgkin's lymphoma.
- Steroid-resistant cells exhibit altered receptors, are activation-labile, lysis-defective, or have deficient receptor quantity.
- DNA demethylation can restore steroid sensitivity in lysis-defective resistant cells.
Conclusions:
- Glucocorticoid receptor activation is essential for steroid-induced cell lysis.
- Multiple mechanisms of steroid resistance exist, involving GR quantity, activation, or downstream cellular pathways.
- Understanding these resistance mechanisms is key to optimizing glucocorticoid therapy in leukopathic diseases.