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 Stark; Norbert Kraut; Christopher R. Vakoc; Johannes Zuber

doi:10.1038/nature14898

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

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

349 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 language	English
Pages (from-to)	543-547
Number of pages	5
Journal	Nature
Volume	525
Issue number	7570
DOIs	https://doi.org/10.1038/nature14898
Publication status	Published - 2015 Sept 24

Bibliographical note

Funding Information:
Acknowledgements We thank M. Weißenböck, B. Hopfgartner and M. Fellner for technical support, S.-M. Kula and the IMP/IMBA Molecular Biology Service for help with libraryconstruction,G.Schmauß, T. Lendl,M.Weninger and G.Stengl and the Biooptics Service Facility for FACS; A. Sommer and his team at Campus Science Support Facilities (http://www.csf.ac.at) for Illumina sequencing, S. W. Lowe for reagents and discussions, and all members of the Zuber laboratory for reagents, protocols and discussions. This research was funded by a Starting Grant of the European Research Council(ERCno.336860; toJ.Z.),SFB grants F4704 andF4710 ofthe Austrian Science Fund (FWF), a Fellowship of the People Programme (Marie Curie Actions) of the European Union (to P.R.). F.M. is an EMBO long-term fellow (EMBO ALTF 491-2014) and research in the Stark laboratory is supported by an ERC Starting grant (no. 242922;toA.S.).The Zuberlaboratoryand researchattheIMPisgenerously supported by Boehringer Ingelheim.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

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Rathert, P., Roth, M., Neumann, T., Muerdter, F., Roe, J. S., Muhar, M., Deswal, S., Cerny-Reiterer, S., Peter, B., Jude, J., Hoffmann, T., Boryn, L. M., Axelsson, E., Schweifer, N., Tontsch-Grunt, U., Dow, L. E., Gianni, D., Pearson, M., Valent, P., ... Zuber, J. (2015). Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature, 525(7570), 543-547. https://doi.org/10.1038/nature14898

@article{fde1d7db8af34fb49167e69ba5e4a4ef,

title = "Transcriptional plasticity promotes primary and acquired resistance to BET inhibition",

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.",

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

note = "Funding Information: Acknowledgements We thank M. Wei{\ss}enb{\"o}ck, B. Hopfgartner and M. Fellner for technical support, S.-M. Kula and the IMP/IMBA Molecular Biology Service for help with libraryconstruction,G.Schmau{\ss}, T. Lendl,M.Weninger and G.Stengl and the Biooptics Service Facility for FACS; A. Sommer and his team at Campus Science Support Facilities (http://www.csf.ac.at) for Illumina sequencing, S. W. Lowe for reagents and discussions, and all members of the Zuber laboratory for reagents, protocols and discussions. This research was funded by a Starting Grant of the European Research Council(ERCno.336860; toJ.Z.),SFB grants F4704 andF4710 ofthe Austrian Science Fund (FWF), a Fellowship of the People Programme (Marie Curie Actions) of the European Union (to P.R.). F.M. is an EMBO long-term fellow (EMBO ALTF 491-2014) and research in the Stark laboratory is supported by an ERC Starting grant (no. 242922;toA.S.).The Zuberlaboratoryand researchattheIMPisgenerously supported by Boehringer Ingelheim. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = sep,

day = "24",

doi = "10.1038/nature14898",

language = "English",

volume = "525",

pages = "543--547",

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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

TY - JOUR

T1 - Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

AU - Rathert, Philipp

AU - Roth, Mareike

AU - Neumann, Tobias

AU - Muerdter, Felix

AU - Roe, Jae Seok

AU - Muhar, Matthias

AU - Deswal, Sumit

AU - Cerny-Reiterer, Sabine

AU - Peter, Barbara

AU - Jude, Julian

AU - Hoffmann, Thomas

AU - Boryn, Lukasz M.

AU - Axelsson, Elin

AU - Schweifer, Norbert

AU - Tontsch-Grunt, Ulrike

AU - Dow, Lukas E.

AU - Gianni, Davide

AU - Pearson, Mark

AU - Valent, Peter

AU - Stark, Alexander

AU - Kraut, Norbert

AU - Vakoc, Christopher R.

AU - Zuber, Johannes

N1 - Funding Information: Acknowledgements We thank M. Weißenböck, B. Hopfgartner and M. Fellner for technical support, S.-M. Kula and the IMP/IMBA Molecular Biology Service for help with libraryconstruction,G.Schmauß, T. Lendl,M.Weninger and G.Stengl and the Biooptics Service Facility for FACS; A. Sommer and his team at Campus Science Support Facilities (http://www.csf.ac.at) for Illumina sequencing, S. W. Lowe for reagents and discussions, and all members of the Zuber laboratory for reagents, protocols and discussions. This research was funded by a Starting Grant of the European Research Council(ERCno.336860; toJ.Z.),SFB grants F4704 andF4710 ofthe Austrian Science Fund (FWF), a Fellowship of the People Programme (Marie Curie Actions) of the European Union (to P.R.). F.M. is an EMBO long-term fellow (EMBO ALTF 491-2014) and research in the Stark laboratory is supported by an ERC Starting grant (no. 242922;toA.S.).The Zuberlaboratoryand researchattheIMPisgenerously supported by Boehringer Ingelheim. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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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Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

Abstract

Bibliographical note

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