TY - JOUR
T1 - BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia
AU - van Galen, Joost C
AU - Kuiper, Roland P
AU - van Emst, Liesbeth
AU - Levers, Marloes
AU - Tijchon, Esther
AU - Scheijen, Blanca
AU - Waanders, Esmé
AU - van Reijmersdal, Simon V
AU - Gilissen, Christian
AU - van Kessel, Ad Geurts
AU - Hoogerbrugge, Peter M
AU - van Leeuwen, Frank N
PY - 2010/6/10
Y1 - 2010/6/10
N2 - Resistance to glucocorticoids (GCs) is a major clinical problem in the treatment of acute lymphoblastic leukemia (ALL), but the underlying mechanisms are not well understood. Although mutations in the glucocorticoid receptor (GR) gene can give rise to therapy resistance in vitro, acquired somatic mutations in the GR are rarely encountered in patients. Here we report that the protein encoded by the BTG1 gene, which is frequently deleted in (pediatric) ALL, is a key determinant of GC responsiveness. Using RNA interference, we show that loss of BTG1 expression causes GC resistance both by decimating GR expression and by controlling GR-mediated transcription. Conversely, reexpression of BTG1 restores GC sensitivity by potentiating GC-induced GR expression, a phenomenon known as GR autoinduction. In addition, the arginine methyltransferase PRMT1, a BTG1-binding partner and transcriptional coactivator, is recruited to the GR gene promoter in a BTG1-dependent manner. These results implicate the BTG1/PRMT1 complex in GR-mediated gene expression and reveal that deregulation of a nuclear receptor coactivator complex can give rise to GC resistance. Further characterization of this complex as part of the GR regulatory circuitry could offer novel opportunities for improving the efficacy of GC-based therapies in ALL and other hematologic malignancies.
AB - Resistance to glucocorticoids (GCs) is a major clinical problem in the treatment of acute lymphoblastic leukemia (ALL), but the underlying mechanisms are not well understood. Although mutations in the glucocorticoid receptor (GR) gene can give rise to therapy resistance in vitro, acquired somatic mutations in the GR are rarely encountered in patients. Here we report that the protein encoded by the BTG1 gene, which is frequently deleted in (pediatric) ALL, is a key determinant of GC responsiveness. Using RNA interference, we show that loss of BTG1 expression causes GC resistance both by decimating GR expression and by controlling GR-mediated transcription. Conversely, reexpression of BTG1 restores GC sensitivity by potentiating GC-induced GR expression, a phenomenon known as GR autoinduction. In addition, the arginine methyltransferase PRMT1, a BTG1-binding partner and transcriptional coactivator, is recruited to the GR gene promoter in a BTG1-dependent manner. These results implicate the BTG1/PRMT1 complex in GR-mediated gene expression and reveal that deregulation of a nuclear receptor coactivator complex can give rise to GC resistance. Further characterization of this complex as part of the GR regulatory circuitry could offer novel opportunities for improving the efficacy of GC-based therapies in ALL and other hematologic malignancies.
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Deletion
KW - Gene Expression Regulation, Leukemic
KW - Glucocorticoids/adverse effects
KW - Humans
KW - Male
KW - Multiprotein Complexes/genetics
KW - Neoplasm Proteins/genetics
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Promoter Regions, Genetic/genetics
KW - Protein-Arginine N-Methyltransferases/genetics
KW - RNA Interference
KW - Receptors, Glucocorticoid/agonists
KW - Repressor Proteins/genetics
KW - Transcription, Genetic/drug effects
U2 - 10.1182/blood-2009-05-223081
DO - 10.1182/blood-2009-05-223081
M3 - Article
C2 - 20354172
SN - 0006-4971
VL - 115
SP - 4810
EP - 4819
JO - Blood
JF - Blood
IS - 23
ER -