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BET inhibitor resistance emerges from leukaemia stem cells. | LitMetric

AI Article Synopsis

  • Bromodomain and extra terminal protein (BET) inhibitors are emerging therapies targeting proteins that interact with acetylated chromatin, showing potential effectiveness in treating acute myeloid leukemia (AML).
  • Research on mouse hematopoietic stem cells revealed that resistance to the BET inhibitor I-BET can occur, leading to cross-resistance against various BET inhibitors, and this resistance arises through leukemia stem cells rather than traditional drug metabolism or efflux mechanisms.
  • The study suggests that a reduction in chromatin-bound BRD4 in resistant cells, along with increased Wnt/β-catenin signaling, plays a role in this resistance, pointing to alternative transcription regulation methods and offering insights for improving the clinical use of BET inhibitors.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069604PMC
http://dx.doi.org/10.1038/nature14888DOI Listing

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