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Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

Overview of attention for article published in Nature, September 2015
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (98th percentile)
  • Above-average Attention Score compared to outputs of the same age and source (62nd percentile)

Mentioned by

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12 news outlets
blogs
1 blog
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28 X users
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8 patents
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1 research highlight platform

Citations

dimensions_citation
420 Dimensions

Readers on

mendeley
433 Mendeley
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4 CiteULike
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Title
Transcriptional plasticity promotes primary and acquired resistance to BET inhibition
Published in
Nature, September 2015
DOI 10.1038/nature14898
Pubmed ID
Authors

Philipp Rathert, Mareike Roth, Tobias Neumann, Felix Muerdter, Jae-Seok Roe, Matthias Muhar, Sumit Deswal, Sabine Cerny-Reiterer, Barbara Peter, Julian Jude, Thomas Hoffmann, Łukasz M. Boryń, Elin Axelsson, Norbert Schweifer, Ulrike Tontsch-Grunt, Lukas E. Dow, Davide Gianni, Mark Pearson, Peter Valent, Alexander Stark, Norbert Kraut, Christopher R. Vakoc, Johannes Zuber

Abstract

Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.

X Demographics

X Demographics

The data shown below were collected from the profiles of 28 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 433 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Denmark 3 <1%
Austria 2 <1%
Spain 2 <1%
United States 2 <1%
Japan 2 <1%
Canada 1 <1%
France 1 <1%
Finland 1 <1%
Portugal 1 <1%
Other 0 0%
Unknown 418 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 110 25%
Researcher 99 23%
Student > Master 42 10%
Student > Bachelor 28 6%
Student > Postgraduate 18 4%
Other 56 13%
Unknown 80 18%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 161 37%
Agricultural and Biological Sciences 104 24%
Medicine and Dentistry 33 8%
Pharmacology, Toxicology and Pharmaceutical Science 16 4%
Chemistry 13 3%
Other 26 6%
Unknown 80 18%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 108. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 August 2023.
All research outputs
#383,018
of 25,247,084 outputs
Outputs from Nature
#19,217
of 97,056 outputs
Outputs of similar age
#4,845
of 275,374 outputs
Outputs of similar age from Nature
#376
of 1,001 outputs
Altmetric has tracked 25,247,084 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 97,056 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 102.4. This one has done well, scoring higher than 80% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 275,374 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 98% of its contemporaries.
We're also able to compare this research output to 1,001 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 62% of its contemporaries.