Hematology
Contributions
Type: Publication Only
Background
Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable. However, glucocorticoids (GC) are essential components in its treatment. The antineoplastic actions of glucocorticoids can be partially attributed to glucocorticoid-induced apoptosis.
Aims
The aim of this study was to evaluate the distribution of the 3 prominent glucocorticoid receptor gene polymorphic variants (BclI, N363S, and ER22/23EK) among controls and Philadelphia-negative adult ALL patients. In addition, we aimed to investigate the association between glucocoticoid receptor mRNA isoforms expressions and the response to induction chemotherapy in the studied patients.
Methods
Fifty-two adults with newly diagnosed Philadelphia-negative ALL, aged 18 to 75 years and 30 healthy control subjects were enrolled in this study. Genotyping of BclI, N363S, and ER22/23EK polymorphisms was carried out by polymerase chain reaction restriction fragment–length polymorphism. Glucocoticoid receptor mRNA isoforms expressions were assayed by quantitative real time PCR.
Results
Fifty-two newly diagnosed Philadelphia-negative adult ALL patients were enrolled with a median age of 34 years (range 18-75). They were 35 (67.3%) males and 17 (32.7%) females. The incidences of BclI, N363S, and ER22/23EK polymorphic variants were 44.2%, 5.8% and 1.9% among patients and were 33.3%, 6.7% and 6.7% among controls, respectively with no statistically significant difference. The allelic frequencies of the mutant allele of BclI, N363S, and ER22/23EK polymorphisms in patients were 0.15, 0.02, and 0.004, respectively. The different genotypes of the polymorphisms were not related to glucocorticoid resistance. No association was found between the studied parameters and the expression of beta glucocorticoid receptor (GR) isoform. The alpha GR expression was associated with complete remission (p=0.03). Compared to GC sensitive patients, the expression of gamma GR mRNA was significantly higher in GC resistant patients (p=0.032). Moreover, the expression of gamma GR mRNA was significantly higher in non-responders versus responder patients(p=0.019).
Summary
The BclI polymorphic variants of the GR gene are the most frequent compared to N363S and ER22/23EK polymorphisms in Philadelphia-negative adult ALL patients. Polymorphisms of the GR gene were not associated with the sensitivity to glucocorticoids. Higher alpha GR and lower gamma GR expressions were associated with achievement of complete remission while higher expression of gamma isoform was associated with glucocorticoid resistance. Our data suggest that pretreatment glucocorticoid receptor isoforms expression levels can be useful in predicting response to glucocorticoids and in anticipating achievement of complete remission in Philadelphia-negative adult ALL patients.
Keyword(s): ALL, Expression, Polymorphism
Session topic: Publication Only
Type: Publication Only
Background
Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable. However, glucocorticoids (GC) are essential components in its treatment. The antineoplastic actions of glucocorticoids can be partially attributed to glucocorticoid-induced apoptosis.
Aims
The aim of this study was to evaluate the distribution of the 3 prominent glucocorticoid receptor gene polymorphic variants (BclI, N363S, and ER22/23EK) among controls and Philadelphia-negative adult ALL patients. In addition, we aimed to investigate the association between glucocoticoid receptor mRNA isoforms expressions and the response to induction chemotherapy in the studied patients.
Methods
Fifty-two adults with newly diagnosed Philadelphia-negative ALL, aged 18 to 75 years and 30 healthy control subjects were enrolled in this study. Genotyping of BclI, N363S, and ER22/23EK polymorphisms was carried out by polymerase chain reaction restriction fragment–length polymorphism. Glucocoticoid receptor mRNA isoforms expressions were assayed by quantitative real time PCR.
Results
Fifty-two newly diagnosed Philadelphia-negative adult ALL patients were enrolled with a median age of 34 years (range 18-75). They were 35 (67.3%) males and 17 (32.7%) females. The incidences of BclI, N363S, and ER22/23EK polymorphic variants were 44.2%, 5.8% and 1.9% among patients and were 33.3%, 6.7% and 6.7% among controls, respectively with no statistically significant difference. The allelic frequencies of the mutant allele of BclI, N363S, and ER22/23EK polymorphisms in patients were 0.15, 0.02, and 0.004, respectively. The different genotypes of the polymorphisms were not related to glucocorticoid resistance. No association was found between the studied parameters and the expression of beta glucocorticoid receptor (GR) isoform. The alpha GR expression was associated with complete remission (p=0.03). Compared to GC sensitive patients, the expression of gamma GR mRNA was significantly higher in GC resistant patients (p=0.032). Moreover, the expression of gamma GR mRNA was significantly higher in non-responders versus responder patients(p=0.019).
Summary
The BclI polymorphic variants of the GR gene are the most frequent compared to N363S and ER22/23EK polymorphisms in Philadelphia-negative adult ALL patients. Polymorphisms of the GR gene were not associated with the sensitivity to glucocorticoids. Higher alpha GR and lower gamma GR expressions were associated with achievement of complete remission while higher expression of gamma isoform was associated with glucocorticoid resistance. Our data suggest that pretreatment glucocorticoid receptor isoforms expression levels can be useful in predicting response to glucocorticoids and in anticipating achievement of complete remission in Philadelphia-negative adult ALL patients.
Keyword(s): ALL, Expression, Polymorphism
Session topic: Publication Only