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| Status |
Public on Sep 15, 2015 |
| Title |
Genome wide expression analysis of BET inhibitor resistance [RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Bromodomain and Extra Terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic paradigm by directly targeting epigenetic readers1,2. Early clinical trials have shown significant promise especially in acute myeloid leukaemia (AML)3; therefore the evaluation of resistance mechanisms, an inevitable consequence of cancer therapies, is of utmost importance to optimise the clinical efficacy of these drugs. Using primary murine stem and progenitor cells immortalised with MLL-AF9, we have used an innovative approach to generate 20 cell lines derived from single cell clones demonstrating stable 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 demonstrated to emerge from leukaemia stem cells (LSC). Resistant clones display a leukaemic granulocyte-macrophage progenitor (L-GMP) phenotype (Lin-, Sca-, cKit+, CD34+, Fc³RII/RIII+) and functionally exhibit increased clonogenic capacity in vitro and markedly shorter leukaemia latency in vivo. Chromatin bound BRD4 is globally reduced in resistant cells, however 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 is in part a consequence of increased Wnt/²-catenin signaling. Negative regulation of this pathway results in differentiation of resistant cells into mature leukaemic blasts, inhibition of MYC expression and restoration of sensitivity to I-BET in vitro and in vivo. Finally, we show that the sensitivity of primary human AML cells to I-BET correlates with the baseline expression of Wnt/²-catenin target genes. Together these findings provide novel insights into the biology of AML, highlight the potential therapeutic limitations of BET inhibitors and identify strategies that may overcome resistance and enhance the clinical utility of these unique targeted therapies.
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| Overall design |
Comparison of iBET resistant and sensitive cell lines
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| Contributor(s) |
Dawson M, Chun F |
| Citation(s) |
26367796 |
| Submission date |
Nov 26, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Mark Dawson |
| E-mail(s) |
mark.dawson@petermac.org
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| Organization name |
Peter MacCallum Cancer Centre
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| Street address |
305 Grattan Street
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| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3000 |
| Country |
Australia |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| GSM1555167 |
600 Resistant 5.3S line Rep 1 [RNA-seq] |
| GSM1555168 |
600 Resistant 5.3S line Rep 2 [RNA-seq] |
| GSM1555169 |
600 Resistant 5.3S line Rep 3 [RNA-seq] |
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| This SubSeries is part of SuperSeries: |
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| Relations |
| SRA |
SRP049363 |
| BioProject |
PRJNA268684 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE63681_rnaseq_norm.txt.gz |
391.2 Kb |
(ftp)(http) |
TXT |
| GSE63681_rnaseq_raw.txt.gz |
384.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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