BET inhibitor resistance emerges from leukaemia stem cells Journal Article

Authors: Fong, C. Y.; Gilan, O.; Lam, E. Y. N.; Rubin, A. F.; Ftouni, S.; Tyler, D.; Stanley, K.; Sinha, D.; Yeh, P.; Morison, J.; Giotopoulos, G.; Lugo, D.; Jeffrey, P.; Lee, S. C. W.; Carpenter, C.; Gregory, R.; Ramsay, R. G.; Lane, S. W.; Abdel-Wahab, O.; Kouzarides, T.; Johnstone, R. W.; Dawson, S. J.; Huntly, B. J. P.; Prinjha, R. K.; Papenfuss, A. T.; Dawson, M. A.
Article Title: BET inhibitor resistance emerges from leukaemia stem cells
Abstract: Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies. © 2015 Macmillan Publishers Limited.
Keywords: controlled study; unclassified drug; genetics; leukemia, myeloid, acute; drug dose reduction; nonhuman; animal cell; mouse; animal; cytology; metabolism; animals; mice; cells, cultured; apoptosis; gene expression; nuclear protein; animal experiment; animal model; protein; transcription factor; genetic transcription; in vivo study; transcription, genetic; in vitro study; drug resistance; pathology; drug resistance, neoplasm; cell line, tumor; inhibitor; transcription factors; cancer resistance; nuclear proteins; gene expression regulation; gene expression regulation, neoplastic; hybrid protein; cell culture; neoplastic stem cells; chromatin; epigenesis, genetic; leukemia cell; genes, myc; tumor cell line; cancer stem cell; acute myeloblastic leukemia; hematopoietic stem cells; cell cycle arrest; benzodiazepine derivative; immunophenotyping; hominid; rodent; hematopoietic stem cell; cell clone; beta catenin; genetic epigenesis; transcriptome; clone cells; short hairpin rna; triazoles; oncogene myc; triazole derivative; colony forming unit gm; cross resistance; pigment; clone; molecularly targeted therapy; drug; molecular targeted therapy; blood system disorder; benzodiazepines; azepines; wnt signaling pathway; drug effects; disease resistance; cells and cell components; humans; human; male; female; priority journal; article; antagonists and inhibitors; immortalized cell line; 4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 a][1,4]diazepine 6 acetic acid tert butyl ester; 7 (3,5 dimethyl 4 isoxazolyl) 1,3 dihydro 8 methoxy 1 [1 (2 pyridinyl)ethyl] 2h imidazo[4,5 c]quinolin 2 one; mll af9 fusion protein; pyrvinium embonate; (+)-jq1 compound; azepine derivative; brd4 protein, human; gsk525762a
Journal Title: Nature
Volume: 525
Issue: 7570
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-09-24
Start Page: 538
End Page: 542
Language: English
DOI: 10.1038/nature14888
PUBMED: 26367796
PROVIDER: scopus
Notes: letter -- Export Date: 2 November 2015 -- Source: Scopus
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MSK Authors
  1. Stanley Chun-Wei Lee
    27 Lee