Kinetics of the in vivo expression of glucocorticoid receptor splice variants during prednisone treatment in childhood acute lymphoblastic leukaemia.
BACKGROUND
The in vivo glucocorticoid response in childhood acute lymphoblastic leukaemia (ALL) correlates with the response to multi-agent chemotherapy. However, it is still unclear, whether the expression levels of glucocorticoid receptor (GR) splice variants facilitate the escape from glucocorticoid-induced apoptosis and hence contribute to glucocorticoid resistance.


METHODS
In the present study, the initial in vivo expression of the common GR (cGR) and its splice variants GR-alpha, GR-gamma and GR-P was determined using a quantitative RT-PCR approach. Two cohorts of glucocorticoid sensitive (prednisone good responder, PGR) and resistant (prednisone poor responder, PPR) patients were compared. The kinetics of GR splice variant expression was measured during 36 hr following the first use of glucocorticoids in seven patients.


RESULTS
The GR splice variant GR-gamma showed the most pronounced differential regulation comparing PPR and PGR patients in both cohorts. GR-alpha and GR-gamma were upregulated faster and to a higher level in PGR as compared to PPR in the in vivo stimulation cohort. Here as well, the most pronounced effect was observed for GR-gamma.


CONCLUSIONS
Differential regulation of the cGR and its splice variants under glucocorticoid treatment rather than the expression level at diagnosis is associated with glucocorticoid response.
Lauten
Melchior
M
Department of Paediatrics and Adolescent Medicine, Division of Paediatric Haematology and Oncology, University of Freiburg, Mathildenstrasse, Freiburg, Germany. melchior.lauten@uniklinik-freiburg.de
Fernandez-Munoz
Ivonne
I
Gerdes
Katrin
K
von Neuhoff
Nils
N
Welte
Karl
K
Schlegelberger
Brigitte
B
Schrappe
Martin
M
Beger
Carmela
C
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D011241:Prednisone / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018931:Antineoplastic Agents, Hormonal; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D011241:Prednisone