Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

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

Research output: Contribution to journalArticle

197 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)543-547
Number of pages5
JournalNature
Volume525
Issue number7570
DOIs
Publication statusPublished - 2015 Sep 24

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Leukemia
Proteins
Acute Myeloid Leukemia
Chromatin
Chromatin Immunoprecipitation
Nucleic Acid Regulatory Sequences
Hematologic Neoplasms
RNA Interference
Neoplasms
Biomarkers
Clinical Trials
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

Rathert, P., Roth, M., Neumann, T., Muerdter, F., Roe, J. S., Muhar, M., ... Zuber, J. (2015). Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature, 525(7570), 543-547. https://doi.org/10.1038/nature14898
Rathert, Philipp ; Roth, Mareike ; Neumann, Tobias ; Muerdter, Felix ; Roe, Jae Seok ; Muhar, Matthias ; Deswal, Sumit ; Cerny-Reiterer, Sabine ; Peter, Barbara ; Jude, Julian ; Hoffmann, Thomas ; Boryn, Lukasz M. ; Axelsson, Elin ; Schweifer, Norbert ; Tontsch-Grunt, Ulrike ; Dow, Lukas E. ; Gianni, Davide ; Pearson, Mark ; Valent, Peter ; Stark, Alexander ; Kraut, Norbert ; Vakoc, Christopher R. ; Zuber, Johannes. / Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. In: Nature. 2015 ; Vol. 525, No. 7570. pp. 543-547.
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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.",
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Rathert, P, Roth, M, Neumann, T, Muerdter, F, Roe, JS, Muhar, M, Deswal, S, Cerny-Reiterer, S, Peter, B, Jude, J, Hoffmann, T, Boryn, LM, Axelsson, E, Schweifer, N, Tontsch-Grunt, U, Dow, LE, Gianni, D, Pearson, M, Valent, P, Stark, A, Kraut, N, Vakoc, CR & Zuber, J 2015, 'Transcriptional plasticity promotes primary and acquired resistance to BET inhibition', Nature, vol. 525, no. 7570, pp. 543-547. https://doi.org/10.1038/nature14898

Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. / Rathert, Philipp; Roth, Mareike; Neumann, Tobias; Muerdter, Felix; Roe, Jae Seok; Muhar, Matthias; Deswal, Sumit; Cerny-Reiterer, Sabine; Peter, Barbara; Jude, Julian; Hoffmann, Thomas; Boryn, Lukasz M.; Axelsson, Elin; Schweifer, Norbert; Tontsch-Grunt, Ulrike; Dow, Lukas E.; Gianni, Davide; Pearson, Mark; Valent, Peter; Stark, Alexander; Kraut, Norbert; Vakoc, Christopher R.; Zuber, Johannes.

In: Nature, Vol. 525, No. 7570, 24.09.2015, p. 543-547.

Research output: Contribution to journalArticle

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AU - Deswal, Sumit

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AU - Peter, Barbara

AU - Jude, Julian

AU - Hoffmann, Thomas

AU - Boryn, Lukasz M.

AU - Axelsson, Elin

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AU - Pearson, Mark

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AU - Zuber, Johannes

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Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015 Sep 24;525(7570):543-547. https://doi.org/10.1038/nature14898