BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia.

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.

[1]  D. Aswad,et al.  Regulation of transcription by a protein methyltransferase. , 1999, Science.

[2]  Leslie L Robison,et al.  Acute lymphoblastic leukaemia , 2018, Radiopaedia.org.

[3]  H. Beug,et al.  FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1 , 2004, The Journal of cell biology.

[4]  Martin J Firth,et al.  Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism , 2009, British Journal of Cancer.

[5]  M. Ffrench,et al.  BTG1, a member of a new family of antiproliferative genes. , 1992, The EMBO journal.

[6]  A. Puisieux,et al.  BTG2, its family and its tutor. , 2004, Bulletin du cancer.

[7]  J. Hehir-Kwa,et al.  High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression , 2007, Leukemia.

[8]  A. Hall,et al.  Loss of heterozygosity and somatic mutations of the glucocorticoid receptor gene are rarely found at relapse in pediatric acute lymphoblastic leukemia but may occur in a subpopulation early in the disease course. , 2005, Cancer research.

[9]  S. Malik,et al.  Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation. , 2006, Molecular cell.

[10]  T. Voeltzel,et al.  The Leukemia-associated Protein Btg1 and the p53-regulated Protein Btg2 Interact with the Homeoprotein Hoxb9 and Enhance Its Transcriptional Activation* , 2000, The Journal of Biological Chemistry.

[11]  R. Evans,et al.  Multiple and cooperative trans-activation domains of the human glucocorticoid receptor , 1988, Cell.

[12]  R. Kofler,et al.  The molecular basis of glucocorticoid-induced apoptosis of lymphoblastic leukemia cells , 2000, Histochemistry and Cell Biology.

[13]  S. Armstrong,et al.  Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells. , 2005, Blood.

[14]  M. Haber,et al.  High level resistance to glucocorticoids, associated with a dysfunctional glucocorticoid receptor, in childhood acute lymphoblastic leukemia cells selected for methotrexate resistance , 2001, Leukemia.

[15]  S. Tsuzuki,et al.  Genetic abnormalities involved in t(12;21) TEL–AML1 acute lymphoblastic leukemia: Analysis by means of array‐based comparative genomic hybridization , 2007, Cancer science.

[16]  R. Kofler,et al.  Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance , 2004, Cell Death and Differentiation.

[17]  John Calvin Reed,et al.  Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays. , 2002, Biochemical and biophysical research communications.

[18]  T. Voeltzel,et al.  Relationships of the Antiproliferative Proteins BTG1 and BTG2 with CAF1, the Human Homolog of a Component of the Yeast CCR4 Transcriptional Complex , 2001, The Journal of Biological Chemistry.

[19]  W. Liu,et al.  Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. , 1999, Cancer research.

[20]  S. Matsuda,et al.  In search of a function for the TIS21/PC3/BTG1/TOB family , 2001, FEBS letters.

[21]  D. DeFranco,et al.  Coactivators and nuclear receptor transactivation , 2008, Journal of cellular biochemistry.

[22]  C. Allis,et al.  Methylation of Histone H4 at Arginine 3 Facilitating Transcriptional Activation by Nuclear Hormone Receptor , 2001, Science.

[23]  S. Scherer,et al.  On the molecular architecture of myelinated fibers , 2000, Histochemistry and Cell Biology.

[24]  Huiling He,et al.  Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced Apoptosis* , 2003, Journal of Biological Chemistry.

[25]  K. Nagata,et al.  SET-mediated Promoter Hypoacetylation Is a Prerequisite for Coactivation of the Estrogen-responsive pS2 Gene by PRMT1* , 2006, Journal of Biological Chemistry.

[26]  W. Tissing,et al.  GeneticVariations in the Glucocorticoid Receptor GeneAre Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia , 2005 .

[27]  R. Crazzolara,et al.  Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia. , 2006, Blood.

[28]  A. Hall,et al.  Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  H R Herschman,et al.  PRMT1 Is the Predominant Type I Protein Arginine Methyltransferase in Mammalian Cells* , 2000, The Journal of Biological Chemistry.

[30]  M. Cleary,et al.  Protein arginine-methyltransferase-dependent oncogenesis , 2007, Nature Cell Biology.

[31]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[32]  W. Tissing,et al.  Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL. , 2006, Blood.

[33]  F. Casas,et al.  Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation , 2005, Oncogene.

[34]  H. Stunnenberg,et al.  Identification of novel functional TBP‐binding sites and general factor repertoires , 2007, The EMBO journal.

[35]  J. Harmon,et al.  Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in vivo. , 2000, Cancer research.

[36]  J. Mizuguchi,et al.  Role for Btg1 and Btg2 in growth arrest of WEHI-231 cells through arginine methylation following membrane immunoglobulin engagement. , 2007, Experimental cell research.

[37]  B. Deroo,et al.  Glucocorticoid receptor-mediated chromatin remodeling in vivo , 2001, Oncogene.

[38]  Christopher B. Miller,et al.  BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros , 2008, Nature.

[39]  W. Tissing,et al.  Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia , 2003, Leukemia.

[40]  Sharmistha Pal,et al.  Interplay between chromatin remodelers and protein arginine methyltransferases , 2007, Journal of cellular physiology.

[41]  S. Clarke,et al.  The Mammalian Immediate-early TIS21 Protein and the Leukemia-associated BTG1 Protein Interact with a Protein-arginine N-Methyltransferase* , 1996, The Journal of Biological Chemistry.

[42]  C. Dehay,et al.  Interaction of PRMT1 with BTG/TOB proteins in cell signalling: molecular analysis and functional aspects , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[43]  C. Riccardi,et al.  GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling. , 2007, The Journal of clinical investigation.

[44]  S. Fiorucci,et al.  The Methyl Transferase PRMT1 Functions as Co-Activator of Farnesoid X Receptor (FXR)/9-cis Retinoid X Receptor and Regulates Transcription of FXR Responsive Genes , 2005, Molecular Pharmacology.