BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia

Joost C van Galen, Roland P Kuiper, Liesbeth van Emst, Marloes Levers, Esther Tijchon, Blanca Scheijen, Esmé Waanders, Simon V van Reijmersdal, Christian Gilissen, Ad Geurts van Kessel, Peter M Hoogerbrugge, Frank N van Leeuwen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)4810-9
Aantal pagina's10
TijdschriftBlood
Volume115
Nummer van het tijdschrift23
DOI's
StatusGepubliceerd - 10 jun. 2010
Extern gepubliceerdJa

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